Abstract

Objectives: We examined the possible enhancement of cognitive decline after ischemic brain damage with amyloid-β (Aβ) injection, focusing on the roles of angiotensin II type 2 (AT2) receptor in vascular smooth muscle cells (VSMC). Methods: Adult male wild-type mice (WT) or the mice with VSMC-specific AT2 receptor overexpression (smAT2) were used. Mice were subjected to intracerebroventricular (ICV) injection of Aβ1–40. Ischemic brain injury was induced by bilateral common carotid artery occlusion (BCCAO) after Aβ injection. Cognitive function was evaluated by the Morris water maze test. Results: ICV injection of Aβ in WT showed impaired cognitive function, whereas BCCAO did not decline significantly cognitive function. In contrast, BCCAO following Aβ injection exhibited more marked cognitive impairment compared to Aβ injection alone in concert with the increases in NADPH oxidase activity, expressions of NADPH oxidase subunit p22phox, p40phox and inflammatory cytokine MCP-1, IL1-β in the hippocampus. BCCAO significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ injection did not increase the neuron pyknosis in the hippocampus, whereas the number of neuron pyknosis was increased significantly with BCCAO. On the other hand, smAT2 did not show cognitive impairment, the changes of the expression for NADPH oxidase subunits, inflammatory cytokines and neuron pyknosis induced by BCCAO with/without Aβ injection in WT. Conclusion: Ischemic brain damage could enhance Aβ-induced cognitive impairment with possible involvements of enhanced oxidative stress, inflammation, neuron degeneration, and breakdown of RAGE-mediated Aβ clearance. AT2 receptor activation in VSMC might play preventive roles in this cognitive decline.

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