Multiple lines of evidence implicate β-amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Aβ is involved remain unclear. Addition of Aβ to the extracellular space can be neurotoxic. Intraneuronal Aβ42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Aβ42 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 thein vivolocalization and accumulation of Aβ42 with time in culture. Furthermore, we demonstrate that Aβ42 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 Aβ42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.

Increasing evidence links intraneuronal β-amyloid (Aβ₄₂) accumulation with the pathogenesis of Alzheimer’s disease (AD). In Aβ precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of Aβ₄₂occurs especially in multivesicular bodies (MVBs). We hypothesized that this impairs the MVB sorting pathway. We used the trafficking of the epidermal growth factor receptor (EGFR) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons. We report that, during EGF stimulation, APP mutant neurons demonstrated impaired inactivation, degradation, and ubiquitination of EGFR. EGFR degradation is dependent on translocation from MVB outer to inner membranes, which is regulated by the ubiquitin-proteasome system (UPS). We provide evidence that Aβ accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby Aβ accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.

A growing body of evidence suggests a relationship between oxidative stress and β‐amyloid (Aβ) peptide accumulation, a hallmark in the pathogenesis of Alzheimer's disease (AD). However, a direct causal relationship between oxidative stress and Aβ pathology has not been established in vivo. Therefore, we crossed mice with a knockout of one allele of manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme, with Tg19959 mice, which overexpress a doubly mutated human β‐amyloid precursor protein (APP). Partial deficiency of MnSOD, which is well established to cause elevated oxidative stress, significantly increased brain Aβ levels and Aβ plaque burden in Tg19959 mice. These results indicate that oxidative stress can promote the pathogenesis of AD and further support the feasibility of antioxidant approaches for AD therapy.