Recent evidence suggests that treatment with certain antihypertensive drugs may decrease the incidence of Alzheimer's disease (AD), while other work has failed to support this finding. We hypothesized that the apparent inconsistency could be due, in part, to unknown pharmacological features exerted by subsets of antihypertensive drugs. Based on this consideration, we initiated a high throughput screening of 55 antihypertensive drugs, which encompass almost all of the prescribed antihypertensive drugs representing all the clinically relevant antihypertensive pharmacological classes available. Excitingly, we identified 7 clinically prescribed antihypertensive drugs that significantly reduce the accumulation of total AD-type ?-amyloid (A?) in vitro and, as recently found, also in vivo in response to treatment with propranolol-HCI, nicardipine-HCI, losartan in Tg2576 mice, even when these drugs were delivered in a short term dosing regimen at concentrations ~2-3 folds lower than the recommended dose for hypertension in the absence of hypotensive side effects. Moreover, consistent, in part with a central role of high-molecular-weight (HMW)- soluble oligomeric A? species in the development of AD-type cognitive impairment, we found that coincidental with attenuation of memory deterioration, long-term valsartan, another antihypertensive drug with A? lowering properties identified in our high-throughput drug screening, significantly reduces ApMo/Api-42 and HMW soluble A? oligomeric content in the brain and plasma when delivered at subclinical doses. Finally, in molecular topological studies assessing the structural basis of Ap-lowering activity amongst the originally 55 antihypertensive-A? lowering agents screened, allowed us to identify 32 novel molecules that we plan to further characterize as novel Ap-lowering lead compounds. Collectively, the proposed studies in this revised U01 application will allow to continue the preclinical characterization of a select group of seven antihypertensive-A? lowering drugs in vivo for the treatment of AD (Aims 1-2) while in molecular topological studies we will continue the refinement of 32 refined A? lowering lead compounds as novel AP lowering agents for the treatment of AD.
