Identification of antihypertensive drugs which inhibit amyloid-beta protein oligomerization

Recent studies suggest that certain cardiovascular antihypertensive agents decrease the incidence of Alzheimer's disease. Based on this evidence and the fact that Abeta aggregation into high-molecular-weight-soluble oligomeric Abeta 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 Abeta oligomers. High throughput screening of 55 commercially available antihypertensive drugs identified four compounds that significantly reduced Abeta(1-42) 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 Abeta lowering activities in primary neuron cultures generated from Tg2576 mouse embryos. However, furosemide, nitrendipine and candesartan cilextil prevented oligomerization of both Abeta(1-40) and Abeta(1-42) in vitro. Furosemide also dissociated pre-aggregated Abeta(1-42) oligomers. Furthermore, short term furosemide treatment resulted in decreased amount of Abeta oligomers in the brain of Tg2576 mice. Our studies suggest that certain antihypertensive compounds may prevent AD-type neuropathology through inhibition of Abeta oligomer formation.