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

Abstract

Background: 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 (AT 2) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit. Methods: Adult male wild-type mice (WT) and mice with VSMC-specific AT 2 receptor overexpression (smAT 2) 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. Results: Aβ 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, smAT 2 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.

Deeper cerebral hypoperfusion leads to spatial cognitive impairment in mice

“…As mouse stain could not survive from the permanent BCCA ligation,11 temporary ligation of CCAs was a common procedure to construct VCI in mice in many studies 16. Studies using the tBCCAO model demonstrated that a 5–20 min ligation of bilateral whole-brain ischaemia caused obvious neuropath physiological changes, such as blood–brain barrier breakdown, white matter injury and early or late hippocampal neuronal damage,5 17 18 as well as decreased spatial memory and learning function 19. In our study, mice subject to bilateral transient whole-brain ischaemia showed about 90% reduction of CBF along with acute (up to 2 weeks’ postoperation) but restorable (restored after 4 weeks) spatial cognitive impairment.…”

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors

“…Using cell-based assays, ET-1 overexpression in reactive astrocytes has been shown to amplify Aβ production (Hung et al, 2015). Aβ accretion contributes to the development of cognitive deficits by impairing the receptor for advanced glycation endproducts (RAGE)-mediated Aβ clearance, which exacerbates inflammation, oxidative stress, and neurodegeneration (Min et al, 2020). These findings indicate that ET-1 upregulation after ischemic stroke is tightly associated with Aβ production and deposition and has considerable effects on excitotoxicity and BBB integrity.…”

Neurovascular Reactivity in Tissue Scarring Following Cerebral Ischemia

“…Remarkably, astrocyte reactivity following ischemia is also associated with endothelin-1 (ET-1)-meadited deposition of amyloid-β (Aβ) (103). Accretion of this protein is linked to diminished Aβ clearance by glial RAGE receptors and the progress of longterm cognitive deficits (104).…”