Multiple lines of evidence implicate ␤-amyloid (A␤) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby A␤ is involved remain unclear. Addition of A␤ to the extracellular space can be neurotoxic. Intraneuronal A␤42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain A␤42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of A␤42 with time in culture. Furthermore, we demonstrate that A␤42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These A␤42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.

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