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(American Journal of Pathology. 2002;161:1869-1879.)
© 2002 American Society for Investigative Pathology

Intraneuronal Alzheimer Aß42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology

Reisuke H. Takahashi^*, Teresa A. Milner^*, Feng Li^*, Ellen E. Nam^*, Mark A. Edgar, Haruyasu Yamaguchi, M. Flint Beal^*, Huaxi Xu, Paul Greengard and Gunnar K. Gouras^*

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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