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