Abstract
Objectives: Amyloid-β (Aβ) deposition in brain and cerebral vessels accelerates the pathogenesis of Alzheimer’s disease and vascular cognitive impairment. We examined possibilities that cerebral ischemia worsens Aβ infusion-mediated cognitive decline, and that angiotensin II type 2 (AT 2 ) receptor stimulation in vascular smooth muscle cells (VSMC) could ameliorate this cognitive impairment induced by cerebral ischemia and Aβ. Methods: Adult male wild-type mice (WT) and the mice with VSMC-specific AT 2 receptor overexpression (smAT 2 ) were used. Mice were subjected to intracerebroventricular (ICV) injection of Aβ1-40. Cerebral ischemia was induced by 15 minutes of bilateral common carotid artery occlusion (BCCAO) 24 hours after Aβ injection. Cognitive function was evaluated by Morris water maze test 3 weeks after Aβ injection. Results: ICV injection of Aβ in WT showed impaired cognitive function (arriving time to platform at day 5: control, 26.53±4.46 sec; Aβ, 65.35±7.44 sec), whereas BCCAO did not decline significantly cognitive function. In contrast, BCCAO following Aβ injection exhibited more marked cognitive impairment (84.27±8.00 sec) compared to Aβ injection alone in concert with the increases in superoxide anion production, NADPH oxidase activity, expressions of NADPH oxidase subunit p 22 phox , p 40 phox and inflammatory cytokines such as MCP-1, IL1-β in the hippocampus. BCCAO following Aβ injection 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 (control, 6.33±0.88/field; Aβ with BCCAO, 46.33±4.10/field). On the other hand, smAT 2 did not show cognitive impairment, the increases in oxidative stress, inflammation markers and RAGE expression, pyknosis, which were induced by Aβ injection with/without BCCAO in WT. Conclusion: Cerebral ischemia exaggerated Aβ-induced cognitive decline with possible involvements of enhanced oxidative stress, inflammation, neuronal degeneration, and breakdown of RAGE-mediated Aβ clearance. AT 2 receptor activation in VSMC could play preventive roles in this cognitive decline.
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