Intraneuronal Aβ oligomers in the pathogenesis of Alzheimer’s disease

Intraneuronal Aβ oligomers in the pathogenesis of Alzheimer's disease

Takami Tomiyama

Department of Neuroscience, Osaka City University Graduate School of Medicine

Aβ oligomers are believed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, their contribution to other pathological features of AD remains unclear. We decided to address this question by studying phenotypes of APP transgenic mice harboring the E693 (Osaka) mutation which enhances Aβ oligomerization but no fibrillization. The mice (APP_OSK-Tg) displayed intraneuronal accumulation of Aβ oligomers from 8 months, followed by synaptic/cognitive impairment, synapse loss, abnormal tau phosphorylation, glial activation, and neuronal loss, but no amyloid plaque formation even at 24 months. These findings suggest that Aβ oligomers cause not only synaptic alteration but also subsequent neuropathology of AD and that intraneuronal accumulation of Aβ, which has been reported to be an early event in AD, profoundly affects neuronal function and survival. In support of the latter, we found that intracellular Aβ oligomers accumulated in ER, endosomes/lysosomes, and mitochondria and caused ER stress, endosomal/lysosomal leakage, mitochondrial dysfunction, and eventually apoptosis in neurons of APP_OSK-Tg mice. Amyloid plaque formation may be a consequence of biological response to protect neurons from toxic Aβ oligomers by which intracellular Aβ oligomers are concentrated to aggregate into harmless fibrils within endosomes/lysosomes and then are discharged from cells into the extracellular space.

Address correspondence to Dr.Takami Tomiyama, Department of Neuroscience, Osaka City University Graduate School of Medicine (1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan)