Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood- brain barrier. Running title: Dihydropyridines and Alzheimer's disease

Several large population based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer’s disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. In order to determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer's Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB) whereas amlodipine and nifedipine were ineffective showing that the Aβ lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Αβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB.