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

NEUROBIOLOGY OF DISEASE

卷:74

Article

Eleuteri, Simona^1,2  Di Giovanni, Saviana¹  Rockenstein, Edward²  Mante, Mike²  Adame, Antony²  Trejo, Margarita³  Wrasidlo, Wolf²  Wu, Fang⁴  Fraering, Patrick C.⁴  Masliah, Eliezer^2,4  Lashuel, Hilal A.¹ 

[1] Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lab Mol & Chem Biol Neurodegenerat, CH-1015 Lausanne, Switzerland

[2] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA

[4] Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lab Mol & Cellular Biol Alzheimers Dis, CH-1015 Lausanne, Switzerland

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

DOI  :  10.1016/j.nbd.2014.08.017

来源: Elsevier

【 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.

【 授权许可】

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