Abstract P448: Interaction Between Ischemic Brain Injury and Amyloid-β Deposition in Cognitive Decline; Possible Cognitive Protection by AT 2 Receptor Activation

Abstract

Objectives: Cerebrovascular damage could breakdown amyloid-β (Aβ) clearance and accelerate Aβ deposition. We examined the interaction between ischemic brain damage and Aβ deposition in cognitive function, focusing on the roles of angiotensin II type 2 (AT 2 ) receptor in vascular smooth muscle cells (VSMC). Methods: Male wild-type mice (WT) or the mice with VSMC-specific AT 2 receptor overexpression (smAT 2 ) were used. Mice were subjected to ICV injection of Aβ1-40. Ischemic brain injury was induced by bilateral common carotid artery occlusion (BCCAO) 24 hours after Aβ1-40 injection. Three weeks after Aβ1-40 injection, cognitive function was evaluated by the Morris water maze test. Brain samples obtained 8 days after Aβ1-40 injection were used to study the related signals. Results: ICV injection of Aβ1-40 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 alone did not decline significantly cognitive function. In contrast, BCCAO following Aβ1-40 injection exhibited more marked cognitive impairment (84.27±8.00 sec) compared to Aβ injection alone with the increase in expressions of NADPH oxidase subunits such as p22phox and p67phox in the hippocampus of mice. Aβ1-40 injection with BCCAO tended to increase the mRNA levels of inflammatory cytokines such as MCP-1 and TNFα. BCCAO significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ1-40 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 changes of the expression for NADPH oxidase subunits and inflammatory cytokines, and neuron pyknosis, which were induced by BCCAO with/without Aβ1-40 injection in WT. Conclusion: Ischemic brain injury could enhance Aβ-induced cognitive impairment with possible involvement of enhanced oxidative stress, neuron degeneration, and breakdown of RAGE-mediated Aβ clearance. AT 2 receptor activation in VSMC could play inhibitory roles in the cognitive decline induced by ischemic brain damage and Aβ deposition.