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 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 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.

Highlights

  • Overactivity of the classical renin–angiotensin system within the brain has been implicated in the pathogenesis of Alzheimer’s disease (AD)

  • Tests for simple main effects revealed that prior to diminazene aceturate (DIZE) administration, both Tg2576 vehicle (Tg-V) and Tg2576 DIZE (Tg-DIZE) mice did not differ significantly but were both impaired compared to WT vehicle (WT-V) controls (p = 0.0001 and 0.001, respectively) (Fig. 2a)

  • We have shown for the first time that DIZE-mediated enhancement of brain ACE2 activity prevented cognitive decline when administered chronically to young (9–10 months) asymptomatic Tg25676 mice and restored cognitive performance in aged impaired (13–15 months old) Tg2576 mice

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Summary

Introduction

Overactivity of the classical renin–angiotensin system (cRAS) within the brain has been implicated in the pathogenesis of Alzheimer’s disease (AD) (reviewed by [1, 2]). Elevated ACE1 activity and higher levels of Ang-II and the angiotensin-II type 1 receptor (AT1R) have been reported in human AD brain tissue [3,4,5,6]. Evidence from large epidemiological and clinical studies indicate that some cRAS-targeting anti-hypertensives, including ACE1 inhibitors (ACE-Is) and AT1R receptor blockers (ARBs), reduce the incidence of AD [7,8,9], and can prolong the conversion to MCI and delay the onset of dementia [10,11,12]. Clinical use of anti-hypertensives is associated with improved tau and Aβ indexes in CSF and autopsied brain tissue [11, 13, 14]. Insights from animal models indicate that the protective effects of ACE-Is and ARBS are associated with anti-inflammatory and anti-oxidative stress

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