Targeting Renin-Angiotensin System Against Alzheimer's Disease

Abstract

Renin Angiotensin System (RAS) is a hormonal system that regulates blood pressure and fluid balance through a coordinated action of renal, cardiovascular, and central nervous systems. In addition to its hemodynamic regulatory role, RAS involves in many brain activities, including memory acquisition and consolidation. This review has summarized the involvement of RAS in the pathology of Alzheimer's disease (AD), and the outcomes of treatment with RAS inhibitors. We have discussed the effect of brain RAS in the amyloid plaque (Aβ) deposition, oxidative stress, neuroinflammation, and vascular pathology which are directly and indirectly associated with AD. Angiotensin II (AngII) via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP) mRNA, β-secretase activity, and presenilin expression. Similarly, it was associated with tau phosphorylation, and reactive oxygen species generation. However, these effects are counterbalanced by Ang II mediated AT2 signaling. The protective effect observed with angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) could be as the result of inhibition of Ang II signaling. ARBs also offer additional benefit by shifting the effect of Ang II toward AT2 receptor. To conclude, targeting RAS in the brain may benefit patients with AD though it still requires further in depth understanding.

Keywords: ACEI; AD; ARB; RAS; amyloid β; inflammation; oxidative stress; vascular disease.

FIGURE 1

Ang-II induces oxidative stress, inflammation and vascular disease via AT1R. Consequently, it causes accumulation of amyloid-β resulting Alzheimer’s disease. However, AT2 R signaling produces beneficial effect including learning and memory. ARBs inhibit AT1R signaling and this shifts the action of Ang-II toward the beneficial pathway (AT2R signaling). ACEIs, Angiotensin converting enzyme inhibitors; ARBs, Angiotensin Receptor blockers; AT1R, Angiotensin 1 Receptor; AT2R, Angiotensin 2 Receptor; Aβ, Amyloid-β; -, negative outcome or blockage; +, positive outcome.