Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

Abstract

of VaD and the development of a clinical therapeutic strategy for VaD are urgent topics for research.Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein (MAP) kinase kinase kinase family, activates MAP kinase kinases, which in turn activate p38 and C-Jun N-terminal (JNK) MAP kinase. Objective-There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions. Approach and Results-A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCASinduced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1 −/− ) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1 −/− mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1 −/− mice. Cerebral nitrotyrosine was increased in wild-type and ASK1 −/− BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1 −/− mice. Conclusions-Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through bloodbrain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment. Figure I in the online-only Data Supplement). Our previous reports showed that ASK1 is involved in angiotensin II-induced vascular endothelial dysfunction and apoptosis, 10 balloon injury-induced vascular neointima formation, 11 and ischemia-induced angiogenesis. 12The potential role of ASK1 in cerebral vasculature/small vessels should be further investigated in relation to VaD. Cerebral ischemia increases cerebral oxidative stress levels 13 and vascular cognitive impairment induced by chronic cerebral ischemia is associated with BBB disruption.14-16 The BBB consists of endothelial cells, basal lamina matrix, astrocyte end-feet, and pericytes. Therefore, in the present study, we hypothesized that ASK1 might be involved in oxidative stress-induced BBB disruption because ...

Intracerebroventricular Infusion of Angiotensin-(1–7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease

“…To assess spatial learning and memory function, from 21 days to 26 days after the start of ICV infusion, the Morris water maze test was performed, according to our previous method [17] with a slight modification. Groups were blinded to the examiners.…”

“…Cerebral blood flow (CBF) was measured using a laser speckle blood flow imager (Omega Zone; Omegawave, Tokyo, Japan), as previously described [17]. The skull of each mouse was exposed by a midline scalp incision under 1.5-2.0% isoflurane and the ICV infusion cannula and osmotic pump were removed.…”

“…Western blot analysis of brain tissue was performed according to our previous method [17]. Primary antibodies used were as follows: anti-GAPDH (x5000, Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA); anti-amyloid precursor protein (#MAB348)(x2000, Merck Millipore, MA, USA); anti-phospho-tau (#ab109390) (x500000, Abcam PLC, Cambridge, UK); anti-angiotensin-(1-7) Mas receptor (#AAR-013) (x2000, Alomone labs, Ltd., Jerusalem, Israel).…”

Chronic Cerebral Ischemia-Induced Memory Impairment After Inhibition of BDNF by Interleukin-1 Signaling Pathway

“…IL-1β and BDNF in hippocampuses of the IL-1R knock-out mice return to normal levels after 2VO followed by improved working memory of the mice, which proves that decrease in BDNF caused by increased IL-1β in hippocampus is one of the possible mechanisms leading to working memory capacity impairment of mice. Bilateral common carotid artery ligation is currently considered as a good way to produce chronic cerebral ischemia model [7] because the hippocampus is very sensitive to ischemia and bilateral common carotid artery ligation usually leads to memory impairment in mice. This study provides a new insight into the pathogenesis of chronic cerebral ischemia-induced memory impairment and thus a new scientific basis and possible therapeutic regimen for the prevention of memory impairment and improvement of memory when developing chronic cerebral ischemia.…”

“…In this study, wild type (WT) C57 mice (adult males) and interleukin-1 receptor knock-out (IL-1 Receptor Knock Out, IL-1R KO) C57 mice (adult males) of 20 ~ 25g were divided into the following four groups: sham group (n = 8); two-vessel occlusion (2VO) [7] group (n = 8); IL-1R KO-sham group (n = 8); IL-1R KO-two-vessel occlusion (KO-2VO) group (n = 8). Mice in 2VO group and KO-2VO group received fasting for solids and liquids 12 hours before operation and were anesthetized with 10% chloral hydrate at a dose of 4 ml / kg.…”