Accumulating evidence indicates that over-stimulation of angiotensin-converting enzyme 1 (ACE1) activity is associated with β-amyloid (Aβ) and phosphorylated tau (p-tau)-induced apoptosis, oxido-nitrosative neuroinflammatory stress and neurodegeneration in Alzheimer’s disease (AD). Alternatively, activation of the ACE2, the metalloprotease neprilysin (Neutral Endopeptidase; NEP) and the insulin-degrading enzyme (IDE) could oppose the effects of ACE1 activation. We aim to investigate the relationship between ACE1/ACE2/NEP/IDE and amyloidogenic/hyperlipidemic-lipid raft signaling in hyperlipidemic AD model. Induction of AD was performed in ovariectomized female rats with high-fat high fructose diet (HFFD) feeding after 4 weeks following d-galactose injection (150 mg/kg). The brain-penetrating ACE1 inhibitor perindopril (0.5 mg/kg/day, p.o.) was administered on a daily basis for 30 days. Perindopril significantly decreased hippocampal expression of ACE1 and increased expression of ACE2, NEP and IDE. Perindopril markedly decreased Aβ_1–42, improved lipid profile and ameliorated the lipid raft protein markers caveolin1 (CAV1) and flotillin 1 (FLOT1). This was accompanied by decreased expression of p-tau and enhancement of cholinergic neurotransmission, coupled with decreased oxido-nitrosative neuroinflammatory stress, enhancement of blood–brain barrier (BBB) functioning and lower expression of the apoptotic markers glial fibrillary acidic protein (GFAP), Bax and β-tubulin. In addition, perindopril ameliorated histopathological damage and improved learning, cognitive and recognition impairment as well as depressive behavior in Morris water maze, Y maze, novel object recognition and forced swimming tests, respectively. Conclusively, perindopril could improve cognitive defects in AD rats, at least through activation of ACE2/NEP/IDE and inhibition of ACE1 and subsequent modulation of amyloidogenic/hyperlipidemic-lipid raft signaling and oxido-nitrosative stress.

越来越多的证据表明，过度刺激血管紧张素转化酶1（ACE1）的活性与β-淀粉样蛋白（Aβ）和磷酸化tau（p-tau）诱导的凋亡，氧化亚硝化神经炎性应激和神经变性有关。 ）。或者，ACE2，金属蛋白酶中性溶酶（中性内肽酶； NEP）和胰岛素降解酶（IDE）的激活可能与ACE1激活的作用相反。我们旨在调查高脂血症AD模型中ACE1 / ACE2 / NEP / IDE与淀粉样蛋白生成/高脂血症-脂筏信号之间的关系。AD的诱导去卵巢的雌性大鼠4周后下列高脂肪高果糖饮食（HFFD）将执行d-半乳糖注射液（150 mg / kg）。每天服用可穿透脑的ACE1抑制剂培哚普利（0.5 mg / kg /天，口服）30天。培哚普利显着降低ACE1的海马表达并增加ACE2，NEP和IDE的表达。培哚普利显着降低_Aβ1–42，改善脂质谱并改善脂质筏蛋白标记小窝蛋白1（CAV1）和弗洛蒂林1（FLOT1）。这伴随着p-tau蛋白表达的降低和胆碱能神经传递的增强，氧化亚硝化神经炎性应激的降低，血脑屏障（BBB）功能的增强和凋亡标记物胶质纤维酸性蛋白（GFAP）的表达降低， Bax和β-微管蛋白。此外，培哚普利分别改善了莫里斯水迷宫，Y迷宫，新颖物体识别和强迫游泳测试的组织病理学损伤，并改善了学习，认知和识别障碍以及抑郁行为。结论是培哚普利可以改善AD大鼠的认知缺陷，