Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway

Abstract

Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer's disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1-7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1-7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.

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

“…All other mice received equivalent volumes of vehicle (saline) injections. This dose was based on several previous studies showing that the optimal dose of DIZE in inducing ACE2 activity was 15 mg/kg/ day [39,43,44] and a preliminary study of our own across a range of DIZE concentrations by IP that confirmed previous findings (data not shown).…”

“…Specifically, ACE2 activity, predominantly involved in the conversion of Ang-II to Ang-(1-7) [37,38], was reduced by almost 50% in AD cases, which was significantly related to Aβ and Tau levels [35]. In an ovariectomised D-galactose rodent model of ageing and dementia, enhancement of ACE2 activity by administration of DIZE reduced brain Aβ pathology and improved cognitive performance [39]. We now present the first data of the impact of ACE2 enhancement in an established transgenic APP mouse model, Tg2576 mice, in which the timing and onset of Aβ pathology and behavioural abnormalities have been well characterised and recognised to model abnormalities in human AD.…”

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

“…In particular, it can convert Aβ43 to Aβ42, which can then be further metabolized by ACE to the less amyloidogenic Aβ40 (Liu et al, ). More recently, the ACE2 activator diminazene was shown to induce stimulation of the ACE2/angiotensin(1‐7)/mas axis reducing cognitive deficits in AD, most probably through activation of the PI3K/Akt pathway (Kamel et al, ). Furthermore, ACE2 appears to be reduced in the post‐mortem AD brain correlating with amyloid and tau pathology (Kehoe, Wong, Al Mulhim, Palmer, & Miners, ).…”

Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

“…In addition to binding to AT1R, a part of Ang II is hydrolyzed to Ang-(1-7) by ACE2, which plays a neuroprotective role by acting on the MasR, exerting anxiolytic effects [48] and ameliorating memory impairment [49]. Studies have shown that hypertension could induce decreased ACE2 levels and reduced generation of Ang-(1-7) [50].…”