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 disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer 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 Aβ 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.