Renin-Angiotensin System and Alzheimer’s Disease Pathophysiology: From the Potential Interactions to Therapeutic Perspectives

Abstract

New roles of the Renin-Angiotensin System (RAS), apart from fluid homeostasis and Blood Pressure (BP) regulation, are being progressively unveiled, since the discoveries of RAS alternative axes and local RAS in different tissues, including the brain. Brain RAS is reported to interact with pathophysiological mechanisms of many neurological and psychiatric diseases, including Alzheimer’s Disease (AD). Even though AD is the most common cause of dementia worldwide, its pathophysiology is far from elucidated. Currently, no treatment can halt the disease course. Successive failures of amyloid-targeting drugs have challenged the amyloid hypothesis and increased the interest in the inflammatory and vascular aspects of AD. RAS compounds, both centrally and peripherally, potentially interact with neuroinflammation and cerebrovascular regulation. This narrative review discusses the AD pathophysiology and its possible interaction with RAS, looking forward to potential therapeutic approaches. RAS molecules affect BP, cerebral blood flow, neuroinflammation, and oxidative stress. Angiotensin (Ang) II, via angiotensin type 1 receptors may promote brain tissue damage, while Ang-(1-7) seems to elicit neuroprotection. Several studies dosed RAS molecules in AD patients' biological material, with heterogeneous results. The link between AD and clinical conditions related to classical RAS axis overactivation (hypertension, heart failure, and chronic kidney disease) supports the hypothesized role of this system in AD. Additionally, RAStargeting drugs as Angiotensin Converting Enzyme inhibitors (ACEis) and Angiotensin Receptor Blockers (ARBs) seem to exert beneficial effects on AD. Results of randomized controlled trials testing ACEi or ARBs in AD are awaited to elucidate whether AD-RAS interaction has implications on AD therapeutics.

Circulating Angiotensin-(1–7) Is Reduced in Alzheimer’s Disease Patients and Correlates With White Matter Abnormalities: Results From a Pilot Study

“…Plasma Ang-(1-7), on the contrary, might protect against AD-related damages, once it increases cerebral blood flow, reduces bloodbrain barrier permeability, and inhibits inflammation. These theoretical perspectives are extensively discussed in our recent review (Ribeiro et al, 2020).…”

“…Evidence from humans is contrastingly scarce. A recent review found 20 reports of RAS' molecules measured in AD subjects (Ribeiro et al, 2020). Most of these studies were investigating RAS' components in the CNS and thus examined brain tissue or cerebrospinal fluid (CSF), with conflicting results.…”

Coronavirus Disease-2019 Conundrum: RAS Blockade and Geriatric-Associated Neuropsychiatric Disorders

“…The neuroprotective effects of ACEIs and ARBs seem to rely on the anti-inflammatory response exerted by the activation of ACE2/Ang-(1-7) /Mas axis and the decrease in Ang-II inflammatory signaling ( 51 , 89 ). Therefore, the anti-inflammatory effects induced by ACEIs and ARBs may constitute a protective mechanism not only for the lung but also for other organs, including the brain, especially at high-risk subjects as older adults with comorbities ( Figure 1 ).…”

“…The neuroprotective effects were associated with increased Ang (1-7)/Ang II ratio, angiogenic factors, and attenuated oxidative stress in the brain ( 88 ). Moreover, several studies employed pharmacological and/or genetic strategies in order to increase ACE2/Ang-(1-7)/Mas axis activity and revealed protective effects of those RAS components in neuropsychiatric and cerebrovascular conditions [for review see ( 49 , 51 , 89 )]. For instance, intracerebroventricular infusion of Ang-(1-7) for 4 weeks significantly improved cognitive function and cerebrovascular reactivity in 5XFAD mice, a model of AD ( 90 ).…”

“…Like the SARS-CoV-1, the SARS-CoV-2 seems to exploit the angiotensin-converting enzyme 2 (ACE2) receptor to entry the host cells (15). The evidence mainly from pre-clinical studies suggesting that ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), drugs often prescribed for CVD, kidney, and metabolic diseases, might up-regulate circulating and tissue expression of ACE2 (16)(17)(18)(19)(20), raised the question whether those therapies increase SARS-CoV-2 infectivity and COVID-19 severity. Accordingly, some researches proposed the discontinuation of ACEIs and ARBs, both prophylactically and in the context of suspected Covid-19 (6,(21)(22)(23).…”