Abstract
BackgroundTo promote understanding of the pathogenesis of cognitive impairment or dementia, we explored the potential interaction between transient cerebral ischemia and amyloid-β (Aβ) infusion in mediating cognitive decline and examined the possible ameliorative effect of angiotensin II type 2 (AT2) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit.MethodsAdult male wild-type mice (WT) and mice with VSMC-specific AT2 receptor overexpression (smAT2) were subjected to intracerebroventricular (ICV) injection of Aβ1-40. Transient cerebral ischemia was induced by 15 min of bilateral common carotid artery occlusion (BCCAO) 24 h after Aβ injection.ResultsAβ injection in WT induced a cognitive decline, whereas BCCAO did not cause a significant cognitive deficit. In contrast, WT with BCCAO following Aβ injection exhibited more marked cognitive decline compared to Aβ 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)-1β in the hippocampus, and upregulation of RAGE (receptor for advanced glycation end product), an Aβ transporter. BCCAO following Aβ injection further enhanced neuronal pyknosis in the hippocampus, compared with BCCAO or Aβ injection alone. In contrast, smAT2 did not show a cognitive decline, increase in oxidative stress, inflammation, and RAGE level or neuronal pyknosis, which were induced by BCCAO with/without Aβ injection in WT.ConclusionsTransient cerebral ischemia might worsen Aβ infusion-mediated cognitive decline and vice versa, with possible involvement of amplified oxidative stress and inflammation and impairment of the RAGE-mediated Aβ clearance system, contributing to exaggerated neuronal degeneration. AT2 receptor activation in VSMC could play an inhibitory role in this cognitive deficit.
Highlights
Cognitive impairment and dementia are becoming serious health problems globally that impair the quality of life of peoples at all ages; promising strategies for prevention and inhibition of their onset and development are urgently needed [1]
We observed that there was no significant difference in mean swimming speed in each group in both wild-type mice (WT) and vascular smooth muscle cells (VSMC)-Specific angiotensin II type 2 (AT2) receptor overexpression (smAT2) mice, and mean swimming speed was similar between two strains, suggesting that the result of spatial learning and memory was not significantly interfered by the change in swimming ability (Supplemental Figure S2)
We proposed here that in response to transient cerebral ischemia combined with Aβ infusion, AT2 receptor signaling activated by damaged cerebral vessel could act as a crucial blocker for Receptor for advanced glycation end products (RAGE) expression and activation to prevent Aβ excess in the brain contributing to inhibition of cognitive decline
Summary
Cognitive impairment and dementia are becoming serious health problems globally that impair the quality of life of peoples at all ages; promising strategies for prevention and inhibition of their onset and development are urgently needed [1]. An excess of amyloid-β (Aβ) peptide in the brain is well recognized to play a pivotal role in the pathogenesis of Alzheimer’s disease (AD)-related dementia by triggering multiple events such as enhancement of oxidative stress, activation of microglia and astrocytes, and neuroinflammation [2]. Both clinical and animal studies have demonstrated that excessive Aβ could induce cerebrovascular pathologies, such as cerebrovascular atherosclerosis and cerebral amyloid angiopathy (CAA), leading to the onset and exacerbation of vascular cognitive impairment or vascular dementia, and accelerating the development of AD-related dementia [3,4,5,6]. To promote understanding of the pathogenesis of cognitive impairment or dementia, we explored the potential interaction between transient cerebral ischemia and amyloid-β (Aβ) infusion in mediating cognitive decline and examined the possible ameliorative effect of angiotensin II type 2 (AT2) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit
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