Abstract WP289: Interaction Between Stroke and Amyloid-β Deposition in Cognitive Function ~Possible Involvement of Antagonist Effect of AT2Receptor Activation~
Background and Aim: Stroke is known to be causally related with Alzheimer’s disease pathology and amyloid-β (Aβ) deposition has been suggested to induce cerebral amyloid angiopathy resulting in stroke-associated cognitive decline. Angiotensin (Ang) type 1 (AT1) receptor activation impairs cognitive performance, whereas Ang II type 2 (AT2) receptor stimulation has been reported to improve cognitive impairment. We examined the interaction between stroke and Aβ deposition in cognitive function, and the possible antagonist effect of AT2 receptor in vascular smooth muscle cells (VSMC) on this cognitive decline.
Methods: Adult (10-12 weeks old) male wild-type (WT) mice (C57BL/6J mice) or the mice with AT2 receptor overexpression in VSMC (SMAT2) were used. Mice were subjected to intracerebroventricular (ICV) injection of Aβ1-40 following 15 minutes global brain ischemia operation. Three weeks after Aβ1-40 ICV injection, cognitive function of spatial learning memory was evaluated by the Morris water maze test. Brain samples were obtained after behavioral testing, and the expression of inflammatory cytokines and NADPH oxidase subunits were measured by real-time quantitative RT-PCR.
Results: ICV injection of Aβ1-40 in WT mice showed impaired cognitive function. On the other hand, WT mice with transient global brain ischemia did not decline significantly cognitive function. In contrast, WT mice with Aβ1-40 ICV injection with global brain ischemia exhibited more marked cognitive impairment compared with control mice. These results suggested that transient brain ischemia and amyloid-β deposition exerted at least additive effects on cognitive impairment. This cognitive decline was accompanied with increased expressions of inflammatory cytokines such as monocyte chemoattractant protein-1 and NADPH oxidase subunits including p22phox. On the other hand, SMAT2 mice did not show cognitive impairment by global brain ischemia with/without Aβ1-40 ICV injection.
Conclusion: Brain ischemia and amyloid-β deposition induced additive or synergistic effect on cognitive impairment. AT2 receptor activation in VSMC could play an inhibitory role in the cognitive decline induced by brain ischemia and amyloid-β deposition.
Author Disclosures: L. Min: Research Grant; Modest; JSPS Kakenhi Number 26860567. M. Mogi: Research Grant; Modest; JSPS Kakenhi Grant Number 16K10826. K. Tsukuda: None. A. Higaki: None. M. Kukida: None. T. Yamauchi: None. X. Wang: None. H. Bai: None. B. Shan: None. J. Iwanami: Research Grant; Modest; JSPS Kakenhi Grant Number 15K19974. M. Horiuchi: Research Grant; Modest; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Daiichi-Sankyo Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K. K., Shionogi & Co., Ltd., Takeda Pharmaceutical Co. Ltd.
- © 2017 by American Heart Association, Inc.