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

Neurobiology of Disease

Saviana Di Giovanni¹  Mike Mante²  Hilal A. Lashuel²  Margarita Trejo²  Antony Adame²  Fang Wu²  Wolf Wrasidlo³  Patrick C. Fraering⁴  Eliezer Masliah⁴  Simona Eleuteri⁵  Edward Rockenstein⁵ 

[1] Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA;Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA;Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA;Laboratory of Molecular and Cellular Biology of Alzheimer's Disease, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland;Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) CH-1015 Lausanne, Switzerland;

关键词: Alzheimer's disease;    Aβ seeding-mediated aggregation;    Aβ-propagation;    Amyloid protein;    Drug discovery;    Inhibitors;   

DOI  :  

来源: DOAJ

【 摘 要 】

Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aβ nucleated polymerization is essential for Aβ 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 Aβ 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 Aβ 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 Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-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 Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.

【 授权许可】

Unknown