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Intraneuronal Alzheimer Aβ42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology

https://doi.org/10.1016/S0002-9440(10)64463-XGet rights and content

A central question in Alzheimer's disease concerns the mechanism by which β-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular β-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as β-amyloid levels rise, months before the appearance of β-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal β-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that β-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal β-amyloid 42 increased with aging and β-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before β-amyloid plaque pathology, suggesting that intracellular accumulation of β-amyloid plays a crucial role in Alzheimer's disease.

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Supported by the National Institutes of Health (grants NS02037, AG09464, and HL18974), the Alzheimer's Association, the American Academy of Neurology Education and Research Foundation, and Paul Beeson Physician Faculty Scholar Award (to G. K. G.).

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