Therapeutic Implications of Renin-Angiotensin System Modulators in Alzheimer's Dementia

Abstract

The Renin-Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer's dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors in AD. ACEIs, commonly used for hypertension, show promise in AD by reducing angiotensin (Ang) II levels. This reduction is significant as Ang II contributes to neuroinflammation, oxidative stress, and β-amyloid (Aβ) accumulation, all implicated in AD pathogenesis. ARBs, known for vasodilation, exhibit neuroprotection by blocking Ang II receptors, improving cerebral blood flow and cognitive decline in AD models. Renin inhibitors offer a novel approach by targeting the initial RAS step, displaying anti-inflammatory and antioxidant effects that mitigate AD degeneration. Preclinical studies demonstrate RAS regulation's favorable impact on neuroinflammation, neuronal damage, cognitive function, and Aβ metabolism. Clinical trials on RAS modulators in AD are limited, but with promising results, ARBs being more effective that ACEIs in reducing cognitive decline. The varied roles of ACEIs, ARBs, and renin inhibitors in RAS modulation present a promising avenue for AD therapeutic intervention, requiring further research to potentially transform AD treatment strategies.

Keywords: ACE inhibitors; ARBs; Alzheimer dementia; aliskiren; angiotensin II; renin–angiotensin.

Figure 1

The angiotensinogen in the presence of renin is converted to angiotensin (Ang) I. Subsequently, Ang I in the presence of an angiotensin-converting enzyme (ACE) is converted to Ang II, and this activates AT1 receptor (AT1R) and AT2R. The activation of AT1Rs by Ang II causes a series of negative effects, some with repercussions on cognitive status, including the onset of dementia caused by neurotoxicity, neuroinflammation, oxidative stress, beta-amyloid deposits, and hyperphosphorylation of tau proteins. Compounds such as aliskiren inhibit renin, thus decreasing the synthesis of Ang I. Angiotensin-converting enzyme inhibitors (ACEIs) (like ramipril) reduce the potential for the transformation of Ang I into Ang II. AT1R blockers of Ang II (like candesartan) antagonize its effects at the receptor level. These modulators, through their actions, produce a series of therapeutical effects such as anti-inflammatory effects, vasodilatation, lowering blood pressure, reducing oxidative stress, and reducing amyloid deposits, thus providing neuroprotection.