Roles of Brain Angiotensin II in Cognitive Function and Dementia

Abstract

The brain renin-angiotensin system (RAS) has been highlighted as having a pathological role in stroke, dementia, and neurodegenerative disease. Particularly, in dementia, epidemiological studies indicate a preventive effect of RAS blockade on cognitive impairment in Alzheimer disease (AD). Moreover, basic experiments suggest a role of brain angiotensin II in neural injury, neuroinflammation, and cognitive function and that RAS blockade attenuates cognitive impairment in rodent dementia models of AD. Therefore, RAS regulation is expected to have therapeutic potential for AD. Here, we discuss the role of angiotensin II in cognitive impairment and AD. Angiotensin II binds to the type 2 receptor (AT2) and works mainly by binding with the type 1 receptor (AT1). AT2 receptor signaling plays a role in protection against multiple-organ damage. A direct AT2 receptor agonist is now available and is expected to reduce inflammation and oxidative stress and enhance cell differentiation. We and other groups reported that AT2 receptor activation enhances neuronal differentiation and neurite outgrowth in the brain. Here, we also review the effect of the AT2 receptor on cognitive function. RAS modulation may be a new therapeutic option for dementia including AD in the future.

Cardiorenal Metabolic Syndrome and Diabetic Cognopathy

“…The angiotensin receptor subtypes AT 1 R, AT 2 R, and AT 4 R are present in the brain, and AT 4 R is identical to the insulin-regulated aminopeptidase, which is often referred to as the AT 4 R/insulin-regulated aminopeptidase receptor. The brain renin-angiotensin-aldosterone system (RAAS) is important in neural function homeostasis and plays a role in normal memory, consolidation, and retrieval of information; RAAS dysfunction is also an important component in the development of CID [40,41,42,43,44,45,46,47]. Excessive RAAS activation has damaging effects resulting in impaired cognitive function.…”

Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

“…Mounting evidence, mostly from non-CNS experimental paradigms, shows multi-functional roles of Ang II in a number of cellular processes recognised to be involved in the pathogenesis of AD [17]. Central Ang II may influence amyloidogenesis (i.e., formation of Ab) by affecting the gene expression of amyloid (Ab) precursor protein (APP), BACE1 and PSEN1 (where, respectively, APP gives rise to Ab after cleavage by b-(BACE1) and g-(PSEN1) secretase) [26].…”

“…These mechanisms are likely to contribute to the progressive nature of cognitive dysfunction in AD, although Ang II may have an interesting direct beneficial effect on cognitive function when its effects are directed through AT 2 R-mediated signalling pathways that are also attributed to cell differentiation and regeneration [17]. Indeed, mice devoid of the AT 2 R exhibit worse cognitive function than wild-type mice [92], while in rats, AT 2 Rs were upregulated and associated with neuronal survival in response to cerebral ischaemia [93].…”

“…Ang II mediates its blood pressure modulating effect mainly via the angiotensin type 1 receptor (AT 1 R), while its type 2 receptor (AT 2 R), on which less is known, is believed to offer a counterbalancing or moderating role of AT 1 R-induced effects [16]. Additionally, Ang II signalling via AT 2 R has recently been suggested to play a role in protection of the brain by promoting neuronal cell differentiation, regeneration and survival [17]. In the past, Ang II was deemed to be the only effector protein of this cascade; however, in more recent years, bioactive metabolites of Ang II and a number of putative receptors have been identified whose functions are being investigated.…”

Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer’s Disease

“…They regulate blood-brain barrier (BBB) permeability [12] and are linked to neuroinflammation, neuronal differentiation and neurite growth [13]. Importantly, AD patients taking angiotensin receptor blockers were found to have reduced AD-related pathology postmortem [14].…”