Angiotensin-converting enzyme as a potential target for treatment of Alzheimer's disease: inhibition or activation?

The accumulation of the amyloid beta-protein (Abeta), the main constituent of the 'amyloid plaque', is widely considered to be the key pathological event in Alzheimer's disease (AD). In particular, the accumulation of Abeta42 is the central event triggering neurodegeneration. Reduction of Abeta is now a major therapeutic strategy. However, only a few patients show evidence of increased Abeta production. Thus, defects in proteases that degrade Abeta could underlie some or many cases of familial and sporadic AD. Among the Abeta degrading enzymes, namely, neprilysin (NEP), insulin-degrading enzyme (IDE), endothelin-converting enzyme (ECE) and angiotensin-converting enzyme (ACE), ACE is the most commonly targeted enzyme by inhibitors in elderly populations because it plays a central role in the regulation of blood pressure and hypertension. Genetic, pathological and biochemical studies have associated ACE with AD. This review discusses genetic, molecular and clinical studies that might help explain the relationship between ACE, hypertension, Abeta degradation and AD.