Clusterin Binding Modulates the Aggregation and Neurotoxicity of Amyloid-ß(1-42).

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by the accumulation of amyloid-ß (Aß) aggregates in the brain. Clusterin (CLU), also known as apolipoprotein J, is a potent risk factor associated with AD pathogenesis, in which Aß aggregation is essentially involved. We observed close colocalization of CLU and Aß(1-42) (Aß42) in parenchymal amyloid plaques or vascular amyloid deposits in the brains of human amyloid precursor protein (hAPP)-transgenic Tg2576 mice. Therefore, to elucidate the binding interaction between CLU and Aß42 and its impact on amyloid aggregation and toxicity, the two synthetic proteins were incubated together under physiological conditions, and their structural and morphological variations were investigated using biochemical, biophysical, and microscopic analyses. Synthetic CLU spontaneously bound to different possible variants of Aß42 aggregates with very high affinity (Kd = 2.647 nM) in vitro to form solid CLU-Aß42 complexes. This CLU binding prevented further aggregation of Aß42 into larger oligomers or fibrils, enriching the population of smaller Aß42 oligomers and protofibrils and monomers. CLU either alleviated or augmented Aß42-induced cytotoxicity and apoptosis in the neuroblastoma-derived SH-SY5Y and N2a cells, depending on the incubation period and the molar ratio of CLU:Aß42 involved in the reaction before addition to the cells. Thus, the effects of CLU on Aß42-induced cytotoxicity were likely determined by the extent to which it bound and sequestered toxic Aß42 oligomers or protofibrils. These findings suggest that CLU could influence amyloid neurotoxicity and pathogenesis by modulating Aß aggregation.