ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

Abstract

Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ 42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity,in vitro

“…No ACE2 ENSG00000130234 X -2.3287002 -4.3401745 1.42E-05 0.000171912 ACE2 activation reduces hippocampal soluble Abeta1-42 (Evans et al, 2020), which is in opposition to our results. However, ACE2 can convert Abeta1-43 to Abeta1-42, which can then be converted to Abeta1-40 by ACE (Liu et al, 2014).…”

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension

“…The use of antihypertensive drugs has also been proposed as a strategy for ameliorating amyloid pathology. A recent study in which regulation of the RAS was enhanced through ACE2 in the Tg2676 mice model of AD showed that spatial memory was improved in association with a reduction in soluble and insoluble Aβ in the hippocampus (Evans et al, 2020). Here, however, vascular function was not evaluated.…”

Impact of COVID-19 on Alzheimer’s Disease Risk: Viewpoint for Research Action

“…The reduced incidence of AD found in subjects treated with RAS-targeting anti-hypertensive drugs was attributed to the increased expression of ACE2 in the brain [64][65][66][67][68]. In middle-aged (13-14-month-old) symptomatic AD Tg mice, the activation of ACE2/Ang-(1-7)/Mas axis by diminazene aceturate (DIZE) administration, lowered hippocampal Aβ, neuroinflammation, and restored cognition [69]. Therefore, these findings corroborate a beneficial effect of ACE2 overexpression at CNS even in AD when molecular pathological events are established.…”

“…New findings demonstrate APOE4 acts beyond its well-known roles in influencing Aβ pathology and lipid homeostasis, since it has a strong influence in neuronal inflammation, potentially spreading pathological proteins through the brain. In human postmortem studies, gliosis was found to be significantly associated with APOE4 carriers when quantified in different brain regions using multiple markers of activation, including CD68, Human Leucocyte Antigen-DR isotype, and CD64 [68,69]. Therefore, the interplay between APOEε4 phenotype and innate immune response in the brain following virus infection, such as astrocytes and microglial cells, should be well investigated, as a driving force that sustains neuroinflammation and leads to AD exacerbation.…”

“…• SARS-CoV 2 entry gene (ACE2) is also expressed in the brain [39,40,[64][65][66][67][68][69] Virus neuroinvasion hypothesis • ACE2 upregulation in the brain can be neuroprotective in AD.…”