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From the Departments of Neurology and Neuroscience* and Pathology, Weill Medical College of Cornell University, New York, New York; the Fisher Center for Alzheimer’s Research and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York; and Gunma University School of Health Sciences, Gunma, Japan
A central question in Alzheimer’s disease concerns the mechanism by which ß-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular ß-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as ß-amyloid levels rise, months before the appearance of ß-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal ß-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that ß-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal ß-amyloid 42 increased with aging and ß-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before ß-amyloid plaque pathology, suggesting that intracellular accumulation of ß-amyloid plays a crucial role in Alzheimer’s disease.
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D. Langui, N. Girardot, K. H. El Hachimi, B. Allinquant, V. Blanchard, L. Pradier, and C. Duyckaerts Subcellular Topography of Neuronal A{beta} Peptide in APPxPS1 Transgenic Mice Am. J. Pathol., November 1, 2004; 165(5): 1465 - 1477. [Abstract] [Full Text] [PDF]
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K. H. Gylys, J. A. Fein, F. Yang, D. J. Wiley, C. A. Miller, and G. M. Cole Synaptic Changes in Alzheimer's Disease: Increased Amyloid-{beta} and Gliosis in Surviving Terminals Is Accompanied by Decreased PSD-95 Fluorescence Am. J. Pathol., November 1, 2004; 165(5): 1809 - 1817. [Abstract] [Full Text] [PDF]
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K. S. Vetrivel, H. Cheng, W. Lin, T. Sakurai, T. Li, N. Nukina, P. C. Wong, H. Xu, and G. Thinakaran Association of {gamma}-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes J. Biol. Chem., October 22, 2004; 279(43): 44945 - 44954. [Abstract] [Full Text] [PDF]
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H. Wang, W.-j. Luo, Y.-w. Zhang, Y.-M. Li, G. Thinakaran, P. Greengard, and H. Xu Presenilins and {gamma}-Secretase Inhibitors Affect Intracellular Trafficking and Cell Surface Localization of the {gamma}-Secretase Complex Components J. Biol. Chem., September 24, 2004; 279(39): 40560 - 40566. [Abstract] [Full Text] [PDF]
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Y. Zhang, N. Champagne, L. K. Beitel, C. G. Goodyer, M. Trifiro, and A. LeBlanc Estrogen and Androgen Protection of Human Neurons against Intracellular Amyloid {beta}1-42 Toxicity through Heat Shock Protein 70 J. Neurosci., June 9, 2004; 24(23): 5315 - 5321. [Abstract] [Full Text] [PDF]
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R. H. Takahashi, C. G. Almeida, P. F. Kearney, F. Yu, M. T. Lin, T. A. Milner, and G. K. Gouras Oligomerization of Alzheimer's {beta}-Amyloid within Processes and Synapses of Cultured Neurons and Brain J. Neurosci., April 7, 2004; 24(14): 3592 - 3599. [Abstract] [Full Text] [PDF]
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L.-W. Jin, I. Maezawa, I. Vincent, and T. Bird Intracellular Accumulation of Amyloidogenic Fragments of Amyloid-{beta} Precursor Protein in Neurons with Niemann-Pick Type C Defects Is Associated with Endosomal Abnormalities Am. J. Pathol., March 1, 2004; 164(3): 975 - 985. [Abstract] [Full Text] [PDF]
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J. Magrane, R. C. Smith, K. Walsh, and H. W. Querfurth Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed {beta}-Amyloid in Neurons J. Neurosci., February 18, 2004; 24(7): 1700 - 1706. [Abstract] [Full Text] [PDF]
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S. H. Pasternak, R. D. Bagshaw, M. Guiral, S. Zhang, C. A. Ackerley, B. J. Pak, J. W. Callahan, and D. J. Mahuran Presenilin-1, Nicastrin, Amyloid Precursor Protein, and {gamma}-Secretase Activity Are Co-localized in the Lysosomal Membrane J. Biol. Chem., July 11, 2003; 278(29): 26687 - 26694. [Abstract] [Full Text] [PDF]
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W.-j. Luo, H. Wang, H. Li, B. S. Kim, S. Shah, H.-J. Lee, G. Thinakaran, T.-W. Kim, G. Yu, and H. Xu PEN-2 and APH-1 Coordinately Regulate Proteolytic Processing of Presenilin 1 J. Biol. Chem., February 28, 2003; 278(10): 7850 - 7854. [Abstract] [Full Text] [PDF]
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