The Brain AT2R-a Potential Target for Therapy in Alzheimer's Disease and Vascular Cognitive Impairment: a Comprehensive Review of Clinical and Experimental Therapeutics

Abstract

Dementia is a potentially avertable tragedy, currently considered among the top 10 greatest global health challenges of the twenty-first century. Dementia not only robs individuals of their dignity and independence, it also has a ripple effect that starts with the inflicted individual's family and projects to the society as a whole. The constantly growing number of cases, along with the lack of effective treatments and socioeconomic impact, poses a serious threat to the sustainability of our health care system. Hence, there is a worldwide effort to identify new targets for the treatment of Alzheimer's disease (AD), the leading cause of dementia. Due to its multifactorial etiology and the recent clinical failure of several novel amyloid-β (Aβ) targeting therapies, a comprehensive "multitarget" approach may be most appropriate for managing this condition. Interestingly, renin angiotensin system (RAS) modulators were shown to positively impact all the factors involved in the pathophysiology of dementia including vascular dysfunction, Aβ accumulation, and associated cholinergic deficiency, in addition to tau hyperphosphorylation and insulin derangements. Furthermore, for many of these drugs, the preclinical evidence is also supported by epidemiological data and/or preliminary clinical trials. The purpose of this review is to provide a comprehensive update on the major causes of dementia including the risk factors, current diagnostic criteria, pathophysiology, and contemporary treatment strategies. Moreover, we highlight the angiotensin II receptor type 2 (AT2R) as an effective drug target and present ample evidence supporting its potential role and clinical applications in cognitive impairment to encourage further investigation in the clinical setting.

Keywords: AT2R agonist; Alzheimer’s disease; Angiotensin receptor blocker; Dementia; Renin angiotensin system modulator; Vascular cognitive impairment.

Figure 1.

A useful analogy describing what goes on in an AD brain is that of an inflammatory inferno. Aβ is fundamental in such pathogenesis, as it “fuels” the fire of neuroinflammation, analogous to dry tinder. It gradually accumulates and sets off a sequence of events, with neuroinflammation, oxidative stress and neurovascular damage all leading to cognitive impairment and dementia, similar to an uncontrollable forest fire with neurons for trees. 1) Aβ monomers aggregate to form oligomers, protofibrils, fibrils and eventually plaques. 2) Aβ oligomers activate microglia by binding to their surface RAGEs. These activated microglia release vast amounts of damaging proinflammatory mediators, (including IL-1β, TNF-α, NFκB) and free radicals (like O₂^.), which promote oxidative stress and further amplify inflammation. The escalating oxidative, pro-inflammatory environment promotes NVU injury. It results in 3) progressive endothelial atrophy along with pericyte and astrocyte damage, resulting in BBB disruption. 4) This toxic milieu also damages oligodendrocytes, resulting in demyelination and progressive axon loss. 5) Aβ accumulation also results in tau hyperphosphorylation, which leads to destabilization of microtubules, preventing axonal transport/trafficking of neurotransmitters to synapses, inhibiting impulse transmission. Hyperphosphorylated tau also tends to aggregate and form NFTs, which accumulate in neuronal cell bodies, leading to neurotoxicity and cell death. Excessive Ang II mediated activation of AT1R causes vasoconstriction, which results in cerebral hypoperfusion and hypoxia, with reduced clearance of Aβ and increased inflammation. Ang II mediated activation of AT2R on the other hand results in vasodilation, improved cerebral blood flow, enhanced Aβ clearance with reduced inflammation and oxidative stress. ARBs were shown to preserve cognition both 1) directly by blocking AT1Rs and preventing their damaging effects and 2) indirectly by allowing an unopposed activation of the neuroprotective AT2Rs by the unbound Ang II hence promoting its beneficial effects. AT2R agonists like C21 act by directly activating the AT2R, hence facilitating Aβ clearance and reducing inflammation. AD: Alzheimer’s disease, Aβ: Amyloid-β, Ang II: Angiotensin II, ARBs: AT1R blockers, AT1R: Angiotensin II receptor type 1, AT2R: Angiotensin II receptor type 1, BBB: Blood brain barrier, IL-1β: interleukin-1β NFκB: Nuclear factor kappa B, NFTs: neurofibrillary tangles, NVU: Neurovascular unit, OD: oligodendrocyte, RAGEs: receptors for advanced glycation end products, TNF-α: Tumor necrosis factor alpha