Abstract

Intrinsic optical emissions, such as autofluorescence and second harmonic generation (SHG), are potentially useful for functional fluorescence imaging and biomedical disease diagnosis for neurodegenerative diseases such as Alzheimer’s disease (AD). Here, using multiphoton and SHG microscopy, we identified sources of intrinsic emissions in ex vivo, acute brain slices from AD transgenic mouse models. We observed autofluorescence and SHG at senile plaques as well as characterized their emission spectra. The utility of intrinsic emissions was demonstrated by imaging senile plaque autofluorescence in conjunction with SHG from microtubule arrays to assess the polarity of microtubules near pathological lesions. Our results suggest that tissues from AD transgenic models contain distinct intrinsic emissions, which can provide valuable information about the disease mechanisms.

© 2009 Optical Society of America

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  1. M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
    [Crossref] [PubMed]
  2. M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
    [Crossref] [PubMed]
  3. E. B. Hanlon, L. T. Perelman, E. I. Vitkin, F. A. Greco, A. C. McKee, and N. W. Kowall, “Scattering differentiates Alzheimer disease in vitro,” Opt. Lett. 33, 624–626 (2008).
    [Crossref] [PubMed]
  4. W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
    [Crossref] [PubMed]
  5. K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
    [Crossref] [PubMed]
  6. H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
    [Crossref] [PubMed]
  7. D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
    [Crossref] [PubMed]
  8. A. C. Kwan, D. A. Dombeck, and W. W. Webb, “Polarized microtubule arrays in apical dendrites and axons,” Proc. Natl. Acad. Sci. 105, 11370–11375 (2008).
    [Crossref] [PubMed]
  9. J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5, 305–310. (1981).
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    [PubMed]
  11. M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
    [Crossref]
  12. W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
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    [Crossref] [PubMed]
  14. K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
    [Crossref] [PubMed]
  15. D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
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  21. R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
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  23. B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
    [Crossref] [PubMed]
  24. L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
    [Crossref] [PubMed]
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  26. T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
    [Crossref] [PubMed]
  27. J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
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  28. J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
    [Crossref] [PubMed]
  29. A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
    [Crossref] [PubMed]
  30. R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
    [PubMed]
  31. G. Eichhoff, M. A. Busche, and O. Garaschuk, “In vivo calcium imaging of the aging and diseased brain,” Eur. J. Nucl. Med. Mol. Imaging 35, S99–S106 (2008).
    [Crossref] [PubMed]
  32. T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
    [Crossref] [PubMed]
  33. B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
    [Crossref] [PubMed]
  34. M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
    [Crossref]
  35. J. C. Jung and M. J. Schnitzer, “Multiphoton endoscopy,” Opt. Lett. 28, 902–904 (2003).
    [Crossref] [PubMed]
  36. W. Göbel, J. N. Kerr, A Nimmerjahn, and F. Helmchen, “Miniaturized two-photon microscope based on a flexible coherent fiber and a gradient-index lens objective,” Opt. Lett. 29, 2521–2523 (2004).
    [Crossref] [PubMed]
  37. M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
    [Crossref] [PubMed]
  38. C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
    [Crossref] [PubMed]
  39. C. Zhu, T. M. Breslin, J. Harter, and N. Ramanujam, “Model based and empirical spectral analysis for the diagnosis of breast cancer,” Opt. Express 16, 14961–14978 (2008).
    [Crossref] [PubMed]
  40. J. A. Palero, H. S. de Bruijn, A. van der Ploeg-van den Heuvel, H. J. C. M. Sterenborg, and H. C. Gerritsen, “In vivo nonlinear spectral imaging in mouse skin,” Opt. Express 14, 4395–4402 (2006).
    [Crossref] [PubMed]

2008 (7)

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

E. B. Hanlon, L. T. Perelman, E. I. Vitkin, F. A. Greco, A. C. McKee, and N. W. Kowall, “Scattering differentiates Alzheimer disease in vitro,” Opt. Lett. 33, 624–626 (2008).
[Crossref] [PubMed]

A. C. Kwan, D. A. Dombeck, and W. W. Webb, “Polarized microtubule arrays in apical dendrites and axons,” Proc. Natl. Acad. Sci. 105, 11370–11375 (2008).
[Crossref] [PubMed]

O. A. Shemesh, H. Erez, I Ginzburg, and M. E. Spira, “Tau-induced traffic jam reflect organelles accumulation at points of microtubule polar mismatching,” Traffic 9, 458–471 (2008).
[Crossref] [PubMed]

G. Eichhoff, M. A. Busche, and O. Garaschuk, “In vivo calcium imaging of the aging and diseased brain,” Eur. J. Nucl. Med. Mol. Imaging 35, S99–S106 (2008).
[Crossref] [PubMed]

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

C. Zhu, T. M. Breslin, J. Harter, and N. Ramanujam, “Model based and empirical spectral analysis for the diagnosis of breast cancer,” Opt. Express 16, 14961–14978 (2008).
[Crossref] [PubMed]

2007 (4)

T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
[Crossref] [PubMed]

J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
[Crossref] [PubMed]

B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
[Crossref] [PubMed]

C. Ballatore, V. M. Lee, and J. Q. Trojanowski, “Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders,” Nat. Rev. Neurosci. 8, 663–672 (2007).
[Crossref] [PubMed]

2006 (3)

L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
[Crossref] [PubMed]

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

J. A. Palero, H. S. de Bruijn, A. van der Ploeg-van den Heuvel, H. J. C. M. Sterenborg, and H. C. Gerritsen, “In vivo nonlinear spectral imaging in mouse skin,” Opt. Express 14, 4395–4402 (2006).
[Crossref] [PubMed]

2005 (3)

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
[Crossref] [PubMed]

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

2004 (4)

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
[Crossref] [PubMed]

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

W. Göbel, J. N. Kerr, A Nimmerjahn, and F. Helmchen, “Miniaturized two-photon microscope based on a flexible coherent fiber and a gradient-index lens objective,” Opt. Lett. 29, 2521–2523 (2004).
[Crossref] [PubMed]

2003 (6)

J. C. Jung and M. J. Schnitzer, “Multiphoton endoscopy,” Opt. Lett. 28, 902–904 (2003).
[Crossref] [PubMed]

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

2002 (3)

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21, 35–40 (2002).
[PubMed]

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
[Crossref] [PubMed]

2001 (3)

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

1997 (1)

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

1996 (1)

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

1994 (1)

L. M. Drach, J. Bohl, and H. H. Goebel, “The lipofuscin content of nerve cells of the inferior olivary nucleus in Alzheimer’s disease,” Dementia 5, 234–239 (1994).
[PubMed]

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

1981 (1)

J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5, 305–310. (1981).
[Crossref] [PubMed]

Abrahamson, E. E.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Akbari, Y.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Alpár, A.

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

Andreadis, A.

L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
[Crossref] [PubMed]

Arendt, T.

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

Atwood, C. S.

C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
[Crossref] [PubMed]

Baas, P. W.

L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
[Crossref] [PubMed]

Bacskai, B. J.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

Ballatore, C.

C. Ballatore, V. M. Lee, and J. Q. Trojanowski, “Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders,” Nat. Rev. Neurosci. 8, 663–672 (2007).
[Crossref] [PubMed]

Beal, M. F.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

Bi, W.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Bohl, J.

L. M. Drach, J. Bohl, and H. H. Goebel, “The lipofuscin content of nerve cells of the inferior olivary nucleus in Alzheimer’s disease,” Dementia 5, 234–239 (1994).
[PubMed]

Borchelt, D. R.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Breslin, T. M.

Brückner, M. K.

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

Bruijn, H. S. de

Busche, M. A.

G. Eichhoff, M. A. Busche, and O. Garaschuk, “In vivo calcium imaging of the aging and diseased brain,” Eur. J. Nucl. Med. Mol. Imaging 35, S99–S106 (2008).
[Crossref] [PubMed]

Caccamo, A.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Calignon, A. de

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Capetillo-Zarate, E.

R. H. Takahashi, E. Capetillo-Zarate, M. T. Lin, T. A. Milner, and G. K. Gouras, “Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses,” Neurobiol. Aging, in press (2008).

Carter, C.

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

Chapman, P.

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Chisholm, L.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Chohan, M. O.

B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
[Crossref] [PubMed]

Christie, R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

Christie, R. H.

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

Cole, G.

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Copeland, N. G.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Corral, A.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Deane, R.

T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
[Crossref] [PubMed]

Debnath, M. L.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

DeKosky, S. T.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Denk, W.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

Dickson, D. W.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Diez, M.

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

Dombeck, D. A.

A. C. Kwan, D. A. Dombeck, and W. W. Webb, “Polarized microtubule arrays in apical dendrites and axons,” Proc. Natl. Acad. Sci. 105, 11370–11375 (2008).
[Crossref] [PubMed]

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

Dowson, J. H.

J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5, 305–310. (1981).
[Crossref] [PubMed]

Drach, L. M.

L. M. Drach, J. Bohl, and H. H. Goebel, “The lipofuscin content of nerve cells of the inferior olivary nucleus in Alzheimer’s disease,” Dementia 5, 234–239 (1994).
[PubMed]

Duff, K.

J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
[Crossref] [PubMed]

Eckman, C.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Edgar, M. A.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

Eichhoff, G.

G. Eichhoff, M. A. Busche, and O. Garaschuk, “In vivo calcium imaging of the aging and diseased brain,” Eur. J. Nucl. Med. Mol. Imaging 35, S99–S106 (2008).
[Crossref] [PubMed]

Enz, A.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Erez, H.

O. A. Shemesh, H. Erez, I Ginzburg, and M. E. Spira, “Tau-induced traffic jam reflect organelles accumulation at points of microtubule polar mismatching,” Traffic 9, 458–471 (2008).
[Crossref] [PubMed]

Fisher, P. J.

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

Frey, P.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Games, D.

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

Gan, W. B.

J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
[Crossref] [PubMed]

J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
[Crossref] [PubMed]

Garaschuk, O.

G. Eichhoff, M. A. Busche, and O. Garaschuk, “In vivo calcium imaging of the aging and diseased brain,” Eur. J. Nucl. Med. Mol. Imaging 35, S99–S106 (2008).
[Crossref] [PubMed]

Garcia-Alloza, M.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Gärtner, U.

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

Gerritsen, H. C.

Ghebremedhin, E.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21, 35–40 (2002).
[PubMed]

Ginzburg, I

O. A. Shemesh, H. Erez, I Ginzburg, and M. E. Spira, “Tau-induced traffic jam reflect organelles accumulation at points of microtubule polar mismatching,” Traffic 9, 458–471 (2008).
[Crossref] [PubMed]

Göbel, W.

Goebel, H. H.

L. M. Drach, J. Bohl, and H. H. Goebel, “The lipofuscin content of nerve cells of the inferior olivary nucleus in Alzheimer’s disease,” Dementia 5, 234–239 (1994).
[PubMed]

Golde, T. E.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Gonzales, V.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Gouras, G. K.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

R. H. Takahashi, E. Capetillo-Zarate, M. T. Lin, T. A. Milner, and G. K. Gouras, “Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses,” Neurobiol. Aging, in press (2008).

Greco, F. A.

Greengard, P.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

Gremlich, H. U.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Grundke-Iqbal, I.

B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
[Crossref] [PubMed]

Grutzendler, J.

J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
[Crossref] [PubMed]

J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
[Crossref] [PubMed]

Haass, C.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21, 35–40 (2002).
[PubMed]

Hamilton, R. L.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Han, X.

T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
[Crossref] [PubMed]

Hanlon, E. B.

Hardy, J.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Harigaya, Y.

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Harter, J.

Heikal, A. A.

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
[Crossref] [PubMed]

Helmchen, F.

Helmin, K.

J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
[Crossref] [PubMed]

Heuvel, A. van der Ploeg-van den

Hintersteiner, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Hökfelt, T.

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

Holtzman, D. M.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Hope, C. E.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Hsiao, K.

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Hutton, M.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Hyman, B. T.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

Ikonomovic, M. D.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Ingelsson, M.

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

Iqbal, K.

B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
[Crossref] [PubMed]

Isanski, B. A.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Jaton, A. L.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Jenkins, N. A.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Jones, G.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Jung, J. C.

Kahn, K.

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

Kajdasz, S. T.

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

Kasischke, K. A.

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
[Crossref] [PubMed]

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

Kayed, R.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Kerr, J. N.

Kinzy, W.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Klunk, W. E.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Kneuer, R.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Koenigsknecht-Talboo, J.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Koistinaho, J.

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

Kowall, N. W.

Kwan, A. C.

A. C. Kwan, D. A. Dombeck, and W. W. Webb, “Polarized microtubule arrays in apical dendrites and axons,” Proc. Natl. Acad. Sci. 105, 11370–11375 (2008).
[Crossref] [PubMed]

LaFerla, F. M.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Lare, J. van

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Lee, M. K.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
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C. Ballatore, V. M. Lee, and J. Q. Trojanowski, “Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders,” Nat. Rev. Neurosci. 8, 663–672 (2007).
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Levene, M. J.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

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J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Li, B.

B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
[Crossref] [PubMed]

Li, F.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

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R. H. Takahashi, E. Capetillo-Zarate, M. T. Lin, T. A. Milner, and G. K. Gouras, “Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses,” Neurobiol. Aging, in press (2008).

Lin, W. L.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

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M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Luo, M.

L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
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C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
[Crossref] [PubMed]

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M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

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S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

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J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

McKee, A. C.

McLean, P. J.

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

Metherate, R.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
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T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
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M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Milner, T. A.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

R. H. Takahashi, E. Capetillo-Zarate, M. T. Lin, T. A. Milner, and G. K. Gouras, “Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses,” Neurobiol. Aging, in press (2008).

Molloy, R. P.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

Murphy, M. P.

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Nam, E. E.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
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T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
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M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Nguyen, P. T.

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

Nikitin, A. Y.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
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K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
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S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Palero, J. A.

Paljug, W. R.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Perelman, L. T.

Perry, G.

C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
[Crossref] [PubMed]

Prada, C.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Price, D. L.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

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M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

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L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
[Crossref] [PubMed]

Ramanujam, N.

Ratovitski, T.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
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M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
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M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

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J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
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Schenk, D.

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
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S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

Sisodia, S. S.

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Skipper, L.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Skoch, J.

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

Smith, M. A.

C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
[Crossref] [PubMed]

Spira, M. E.

O. A. Shemesh, H. Erez, I Ginzburg, and M. E. Spira, “Tau-induced traffic jam reflect organelles accumulation at points of microtubule polar mismatching,” Traffic 9, 458–471 (2008).
[Crossref] [PubMed]

Spires, T. L.

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

Spires-Jones, T. L.

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Staufenbiel, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Sterenborg, H. J. C. M.

Stern, E. A.

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

Stoeckli, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

Stuart, G.

B. Sakmann and G. Stuart, “Patch-pipette recordings from the soma, dendrites and, and axon of neurons in brain slices,” in Single-Channel Recording, 2nd ed., B. Sakmann and E. Neher, eds. (Plenum, 1983), pp. 199–211.

Takahashi, R. H.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

R. H. Takahashi, E. Capetillo-Zarate, M. T. Lin, T. A. Milner, and G. K. Gouras, “Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses,” Neurobiol. Aging, in press (2008).

Takano, T.

T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
[Crossref] [PubMed]

Thal, D. R.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21, 35–40 (2002).
[PubMed]

Trojanowski, J. Q.

C. Ballatore, V. M. Lee, and J. Q. Trojanowski, “Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders,” Nat. Rev. Neurosci. 8, 663–672 (2007).
[Crossref] [PubMed]

Tsai, J.

J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
[Crossref] [PubMed]

J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
[Crossref] [PubMed]

Tsopelas, N. D.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Ueberham, U.

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

Vishwasrao, H. D.

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
[Crossref] [PubMed]

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

Vitkin, E. I.

Webb, W. W.

A. C. Kwan, D. A. Dombeck, and W. W. Webb, “Polarized microtubule arrays in apical dendrites and axons,” Proc. Natl. Acad. Sci. 105, 11370–11375 (2008).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
[Crossref] [PubMed]

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

Wiederhold, K. H.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

Williams, R. M.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

Xu, H.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

Yager, D.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Yamaguchi, H.

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

Yang, F.

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Yen, S. H.

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

Younkin, S.

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Yu, W.

L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
[Crossref] [PubMed]

Zhu, C.

Ziolko, S.

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Zipfel, W. R.

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

Zlokovic, B.

T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
[Crossref] [PubMed]

Acta Neuropathol. (1)

B. Li, M. O. Chohan, I. Grundke-Iqbal, and K. Iqbal, “Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau,” Acta Neuropathol. 113, 501–511 (2007).
[Crossref] [PubMed]

Am. J. Pathol. (1)

R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras, “Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology,” Am. J. Pathol. 161, 1869–1879 (2002).
[Crossref] [PubMed]

Ann. N. Y. Acad. Sci. (1)

J. Grutzendler, K. Helmin, J. Tsai, and W. B. Gan, “Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease,” Ann. N. Y. Acad. Sci. 1097, 30–39 (2007).
[Crossref] [PubMed]

Ann. N.Y. Acad. Sci. (1)

T. Takano, X. Han, R. Deane, B. Zlokovic, and M. Nedergaard, “Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease,” Ann. N.Y. Acad. Sci. 1097, 40–50 (2007).
[Crossref] [PubMed]

Brain (1)

M. D. Ikonomovic, W. E. Klunk, E. E. Abrahamson, C. A. Mathis, J. C. Price, N. D. Tsopelas, B. J. Lopresti, S. Ziolko, W. Bi, W. R. Paljug, M. L. Debnath, C. E. Hope, B. A. Isanski, R. L. Hamilton, and S. T. DeKosky, “Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease,” Brain 131, 1630–1645 (2008).
[Crossref] [PubMed]

Brain Res. (1)

A. Alpár, U. Ueberham, M. K. Brückner, G. Seeger, T. Arendt, and U. Gärtner, “Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice,” Brain Res. 1099, 189–198 (2006).
[Crossref] [PubMed]

Clin. Neuropathol. (1)

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21, 35–40 (2002).
[PubMed]

Dementia (1)

L. M. Drach, J. Bohl, and H. H. Goebel, “The lipofuscin content of nerve cells of the inferior olivary nucleus in Alzheimer’s disease,” Dementia 5, 234–239 (1994).
[PubMed]

Eur. J. Nucl. Med. Mol. Imaging (1)

G. Eichhoff, M. A. Busche, and O. Garaschuk, “In vivo calcium imaging of the aging and diseased brain,” Eur. J. Nucl. Med. Mol. Imaging 35, S99–S106 (2008).
[Crossref] [PubMed]

Histopathology (1)

J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5, 305–310. (1981).
[Crossref] [PubMed]

J. Biol. Chem. (1)

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280, 25119–25126 (2005).
[Crossref] [PubMed]

J. Neurophysiol. (1)

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91, 1908–1912 (2004).
[Crossref]

J. Neurosci. (3)

R. H. Christie, B. J. Bacskai, W. R. Zipfel, R. M. Williams, S. T. Kajdasz, W. W. Webb, and B. T. Hyman, “Growth arrest of individual senile plaques in a model of Alzheimer’s disease observed by in vivo multiphoton microscopy,” J. Neurosci. 21, 858–864 (2001).
[PubMed]

T. L. Spires, M. Meyer-Leuhmann, E. A. Stern, P. J. McLean, J. Skoch, P. T. Nguyen, B. J. Bacskai, and B. T. Hyman, “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” J. Neurosci. 25, 7278–7287 (2005).
[Crossref] [PubMed]

L. Qiang, W. Yu, A. Andreadis, M. Luo, and P. W. Baas, “Tau protects microtubules in the axon from severing by katanin,” J. Neurosci. 26, 3120–3129 (2006).
[Crossref] [PubMed]

Nat. Biotechnol. (2)

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, “In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe,” Nat. Biotechnol. 23, 577–583 (2005).
[Crossref] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

Nat. Med. (1)

B. J. Bacskai, S. T. Kajdasz, R. H. Christie, C. Carter, D. Games, P. Seubert, D. Schenk, and B. T. Hyman, “Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy,” Nat. Med. 7, 369–372 (2001).
[Crossref] [PubMed]

Nat. Neurosci. (1)

J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal brances,” Nat. Neurosci. 7, 1181–1183 (2004).
[Crossref] [PubMed]

Nat. Rev. Neurosci. (1)

C. Ballatore, V. M. Lee, and J. Q. Trojanowski, “Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders,” Nat. Rev. Neurosci. 8, 663–672 (2007).
[Crossref] [PubMed]

Nature (1)

M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman, “Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease,” Nature 451, 720–724 (2008).
[Crossref] [PubMed]

Neuron (2)

S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, and F. M. LaFerla, “Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction,” Neuron 39, 409–421 (2003).
[Crossref] [PubMed]

D. R. Borchelt, T. Ratovitski, J. van Lare, M. K. Lee, V. Gonzales, N. A. Jenkins, N. G. Copeland, D. L. Price, and S. S. Sisodia, “Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins,” Neuron 19, 939–945 (1997).
[Crossref] [PubMed]

Neuroscience (1)

M. Diez, J. Koistinaho, K. Kahn, D. Games, and T. Hökfelt, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - initial observations,” Neuroscience 100, 259–286. (2003).
[Crossref]

Opt. Express (2)

Opt. Lett. (3)

Peptides (1)

C. S. Atwood, R. N. Martins, M. A. Smith, and G. Perry, “Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins,” Peptides 23, 1343–1350 (2002).
[Crossref] [PubMed]

Proc. Natl. Acad. Sci. (3)

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100, 7075–7080 (2003).
[Crossref] [PubMed]

D. A. Dombeck, K. A. Kasischke, H. D. Vishwasrao, M. Ingelsson, B. T. Hyman, and W. W. Webb, “Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 100, 7081–7086 (2003).
[Crossref] [PubMed]

A. C. Kwan, D. A. Dombeck, and W. W. Webb, “Polarized microtubule arrays in apical dendrites and axons,” Proc. Natl. Acad. Sci. 105, 11370–11375 (2008).
[Crossref] [PubMed]

Science (4)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305, 99–103 (2004).
[Crossref] [PubMed]

J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science 293, 1487–1491 (2001).
[Crossref] [PubMed]

K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole, “Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice,” Science 274, 99–102 (1996).
[Crossref] [PubMed]

Traffic (1)

O. A. Shemesh, H. Erez, I Ginzburg, and M. E. Spira, “Tau-induced traffic jam reflect organelles accumulation at points of microtubule polar mismatching,” Traffic 9, 458–471 (2008).
[Crossref] [PubMed]

Other (2)

R. H. Takahashi, E. Capetillo-Zarate, M. T. Lin, T. A. Milner, and G. K. Gouras, “Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses,” Neurobiol. Aging, in press (2008).

B. Sakmann and G. Stuart, “Patch-pipette recordings from the soma, dendrites and, and axon of neurons in brain slices,” in Single-Channel Recording, 2nd ed., B. Sakmann and E. Neher, eds. (Plenum, 1983), pp. 199–211.

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Figures (5)

Fig. 1.
Fig. 1.

Autofluorescence and second harmonic emissions from acute hippocampal brain slice of transgenic Alzheimer’s disease mouse models. (a) Autofluorescence, (b) second harmonic emissions, (c) and their overlay of the hippocampus of a 17-month old APPSwe/TauJNPL3 mouse. Senile plaques emit autofluorescence (white arrows) that were morphologically distinct from other sources of intrinsic emissions and were missing from wild-type animals, as shown in (d). Each panel is a mosaic of z-projections of a 50μm thick image stack acquired in 10μm steps. Multiphoton excitation wavelength = 774nm, circular polarization.

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Fig. 2.
Fig. 2.

Senile plaques emit autofluorescence and second harmonic signal. (a) Autofluorescence and (b) second harmonic emissions detected in the entorhinal cortex in acute slices of a 22-month old APPSwe/TauJNPL3 mouse. (c) Overlay of (a) and (b) shows the same large, round structures (appears as yellow in the overlay) emit both the autofluorescence and second harmonic signals, which were then identified to be senile plaques when (d) this brain slice was subsequently fixed and stained with the plaque-specific dye Thioflavin-S. The small, bright specks were lipofuscins, which did not generate second harmonic emission. (e–h) Autofluorescence and second harmonic signal, of unknown molecular origin, were also detected near a blood vessel that was affected by cerebral amyloid angiopathy. Signal could be emitted from a source similar to that in senile plaque or from collagen. Each panel is a z-projection of a 40–60μm thick image stack acquired in 3 or 4μm steps. Multiphoton excitation wavelength = 774nm, circular polarization.

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Fig. 3.
Fig. 3.

Typical emission spectra of senile plaque autofluorescence. (a) The emission spectra of a senile plaque (red trace) and of an adjacent plaque-free region (blue trace) were measured 50μm beneath the surface of an acute slice from an 18-month-old APPSwe mouse. A typical emission spectrum of the senile plaque autofluorescence, excited at 830nm, peaked at ~520nm and showed detectable SHG emissions at 415nm. After acquiring the spectra, this brain slice was fixed and stained with Thioflavin-S. Emission spectrum of one Thioflavin-S-stained senile plaque, obtained at ~10 times less power and 10 times less acquisition time as the autofluorescence, is shown (black trace, normalized) for comparison. (b) The region in the neocortex of the acute slice where the spectra (red and blue boxes) were taken for (a). (c) The emission spectra for four different conditions recorded from the same mouse: i) emission spectrum at senile plaque, excited at 774nm; ii) emission spectrum at a different senile plaque, excited at 774nm, but with quick acquisition to reduce photodamage; iii) emission spectrum at another senile plaque, excited at 830nm; iv) emission spectrum at a plaque-less location, dominated by autofluorescence, presumably from lipofuscin because of the high emission wavelength. Second harmonic peak in iv) is exaggerated because emission intensity was re-scaled. The actual recorded second harmonic peak was weak, see panel (a), and it may be extraneous signal generated when the spectrometer gratings diffract the intense excitation beam. Arrows indicate the locations of the peak emission wavelengths for the autofluorescence.

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Fig. 4.
Fig. 4.

Length and number density of polarized microtubule arrays in area CA1 in Alzheimer’s disease mouse models. (a) Typical autofluorescence (red) and second harmonic emissions (green) in area CA1 from an acute slice of a 21-month-old APPSwe/PS1 mouse. This image is a z-projection of an 18μm thick image stack acquired in 3μm steps. Multiphoton excitation wavelength = 774nm, linear polarization. (b) The length and number density of polarized microtubules in area CA1 of Alzheimer’s disease mouse models (solid dots) and of wild-type mice studied that were over 1 year old (hollow dots). The dotted lines show the trend based on data from a larger set of wild-type mice from our previous study [8].

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Fig. 5.
Fig. 5.

Polarized microtubules in apical dendrites near a senile plaque. A series of images shows second harmonic emissions from polarized microtubules of apical dendrites (green) near an autofluorescent senile plaque (red). The z value denotes the distance to the slice surface. The senile plaque was located in the area CA1 in the hippocampus in an acute slice from a 17-month old APPSwe/TauJNPL3 mouse. Multiphoton excitation wavelength = 774nm, circular polarization.

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