Novel therapeutic strategy for neurodegeneration by blocking A beta seeding mediated aggregation in models of Alzheimer's disease

摘要

A beta accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of A beta nucleated polymerization is essential for A beta fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the A beta seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with A beta seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against A beta-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThyl-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of A beta(42) oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and A beta seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD. (C) 2014 Elsevier Inc. All rights reserved.