Renin-angiotensin system and amyloid β-protein metabolism in the brain

Makoto Michikawa

Department of Alzheimer’s Disease Research, National Center for Geriatrics and Gerontology (NCGG)

　　The accumulation of the amyloid β-protein (Aβ), particularly Aβ42, is considered to be the pathological key event promoting Alzheimer's disease (AD).　The level of Aβ in the brain is regulated by the balance between its generation and degradation/clearance. Thus, the decrease in the Aβ degradation may be involved in the promotion of AD pathology.　Among the Aβ 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 regulation of blood pressure and hypertension.　Genetic, pathologic and biochemical studies have shown the association of ACE with AD development;however, there is discrepancy in previous studies in terms of the effects of ACE inhibiters on AD development, AD pathologies, and AD symptoms.　Our previous studies have shown that ACE not only degrades Aβ, but also converts Aβ42 to Aβ40, and that taking an ACE inhibitor enhances Aβ deposition in APP-Tg mouse brains.　Whereas others have shown that taking ACE inhibitors prevent AD development or attenuates progress in memory impairment.　Taking this discrepancy into account, this review discusses genetic, molecular and clinical studies that may explain the relationship between ACE, Aβ degradation, and AD.

Address correspondent to Dr. Makoto Michikawa:Department of Alzheimer’s Disease Research, National Center for Geriatrics and Gerontology (NCGG) (35 Gengo, Morioka, Obu, Aichi 474-8511, Japan)