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

AbstractMid-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, a nd 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 CN S 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 con firmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ42 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 i n cognit...
Source: Acta Neuropathologica - Category: Neurology Source Type: research