Affiliations: [a] Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA | [b] Department of Neurology, David Geffen School of Medicine, and Molecular Biology Institute and Brain Research Institute, University of California, Los Angeles, CA, USA | [c] GRECC, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
Correspondence:
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Corresponding author: Giulio Maria Pasinetti, M.D., Ph.D., Ichan Research Institute, The Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, NY 10029, USA. Tel.: +1 212 659 8716; +1 212 659 8740; Fax: +1 212 876 9042; E-mail: giulio.pasinetti@mssm.edu.
Abstract: Recent studies suggest that certain cardiovascular antihypertensive agents decrease the incidence of Alzheimer's disease. Based on this evidence and the fact that Aβ aggregation into high-molecular-weight-soluble oligomeric Aβ species is known to directly induce cognitive impairment, we tested the possibility that certain antihypertensive compounds may affect the progression of Alzheimer's disease, at least in part by influencing the formation of Aβ oligomers. High throughput screening of 55 commercially available antihypertensive drugs identified four compounds that significantly reduced Aβ1–42 oligomerization in a dose dependent manner. These four compounds, furosemide (diuretic), nitrendipine (calcium channel blocker), candesartan cilextil (angiotensin II receptor antagonist) and diazoxide (vasodilator) showed no detectable Aβ lowering activities in primary neuron cultures generated from Tg2576 mouse embryos. However, furosemide, nitrendipine and candesartan cilextil prevented oligomerization of both Aβ1–40 and Aβ1–42 in vitro. Furosemide also dissociated pre-aggregated Aβ1–42 oligomers. Furthermore, short term furosemide treatment resulted in decreased amount of Aβ oligomers in the brain of Tg2576 mice. Our studies suggest that certain antihypertensive compounds may prevent AD-type neuropathology through inhibition of Aβ oligomer formation.
