Increasing evidence suggests that the soluble form of the -amyloid peptide (A) pla ys a critical role in the

pathogenesis of Alzheimer's disease. Previously, we re ported that treatment with certain antihypertensive dihydropyridine (DHP) compou nds can mitigate A production in whole cells and reduce rain A urden in a mouse model of Alzheimer's disease. As A clearance across the lood- rain arrier (BBB) is a key regulatory step in the deposition of A in the rain, we examined the ef fect of DHP treatment on A rain clearance. Treatment with certain DHP compounds significantly increased A(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lerc anidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipin e, isradipine, and nifedipine had no effect on A(1-42) BBB transcytosis. In an in vivo paradigm of A clearance across the BBB, peripheral administration of nitren dipine, cilnidipine, and nilvadipine to wild-type animals facilitated the rain clearance of centrally administered exogenous A(1-42), whereas with amlodipine, t here was no effect. We also o served improved cognitive function in mice treated with nilvadipine following central A(1-42) insult. Thus, in addition to the effe ct of certain DHP compounds on A production, we demonstrate that certain DHP comp ounds also facilitate the clearance of A across the BBB. This dual mechanism of a ction may e particularly effective in attenuating A rain urden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease. for more information on the Roskamp Institute and Alzheimers please visit: http://www.mullanalzheimer.com http://www.mullanalzheimer.info http://www.michaelmullan.us www.rfdn.org