Deterioration of cognitive function after transient cerebral ischemia with amyloid-β infusion-possible amelioration of cognitive function by AT2 receptor activation

Abstract

BackgroundTo promote understanding of the pathogenesis of cognitive impairment or dementia, we explored the potential interaction between transient cerebral ischemia and amyloid-beta (A beta) infusion in mediating cognitive decline and examined the possible ameliorative effect of angiotensin II type 2 (AT(2)) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit.MethodsAdult male wild-type mice (WT) and mice with VSMC-specific AT(2) receptor overexpression (smAT(2)) were subjected to intracerebroventricular (ICV) injection of A beta 1-40. Transient cerebral ischemia was induced by 15 min of bilateral common carotid artery occlusion (BCCAO) 24 h after A beta injection.ResultsA beta injection in WT induced a cognitive decline, whereas BCCAO did not cause a significant cognitive deficit. In contrast, WT with BCCAO following A beta injection exhibited more marked cognitive decline compared to A beta injection alone, in concert with increases in superoxide anion production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and expression of p22phox, p40phox, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-1 beta in the hippocampus, and upregulation of RAGE (receptor for advanced glycation end product), an A beta transporter. BCCAO following A beta injection further enhanced neuronal pyknosis in the hippocampus, compared with BCCAO or A beta injection alone. In contrast, smAT(2) did not show a cognitive decline, increase in oxidative stress, inflammation, and RAGE level or neuronal pyknosis, which were induced by BCCAO with/without A beta injection in WT.ConclusionsTransient cerebral ischemia might worsen A beta infusion-mediated cognitive decline and vice versa, with possible involvement of amplified oxidative stress and inflammation and impairment of the RAGE-mediated A beta clearance system, contributing to exaggerated neuronal degeneration. AT(2) receptor activation in VSMC could play an inhibitory role in this cognitive deficit.