RGD Reference Report - Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion. - Rat Genome Database

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Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion.

Authors: Toyama, K  Koibuchi, N  Uekawa, K  Hasegawa, Y  Kataoka, K  Katayama, T  Sueta, D  Ma, MJ  Nakagawa, T  Yasuda, O  Tomimoto, H  Ichijo, H  Ogawa, H  Kim-Mitsuyama, S 
Citation: Toyama K, etal., Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):616-25. doi: 10.1161/ATVBAHA.113.302440. Epub 2013 Dec 26.
RGD ID: 10412307
Pubmed: PMID:24371084   (View Abstract at PubMed)
DOI: DOI:10.1161/ATVBAHA.113.302440   (Journal Full-text)

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. BCAS-induced 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-alpha 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-alpha 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 blood-brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MAP3K5HumanChronic Cerebral Hypoperfusion  ISOMap3k5 (Mus musculus)protein:hyperphosphorylation:brain:RGD 
MAPK14HumanChronic Cerebral Hypoperfusion  ISOMapk14 (Mus musculus)protein:hyperphosphorylation:corpus callosum more ...RGD 
Map3k5MouseChronic Cerebral Hypoperfusion  IEP protein:hyperphosphorylation:brain:RGD 
Map3k5RatChronic Cerebral Hypoperfusion  ISOMap3k5 (Mus musculus)protein:hyperphosphorylation:brain:RGD 
Mapk14RatChronic Cerebral Hypoperfusion  ISOMapk14 (Mus musculus)protein:hyperphosphorylation:corpus callosum more ...RGD 
Mapk14MouseChronic Cerebral Hypoperfusion  IEP protein:hyperphosphorylation:corpus callosum more ...RGD 
MAP3K5Humancognitive disorder  ISOMap3k5 (Mus musculus)associated with Chronic Cerebral HypoperfusionRGD 
MAPK14Humancognitive disorder  ISOMapk14 (Mus musculus)associated with Chronic Cerebral HypoperfusionRGD 
Map3k5Ratcognitive disorder  ISOMap3k5 (Mus musculus)associated with Chronic Cerebral HypoperfusionRGD 
Map3k5Mousecognitive disorder  IMP associated with Chronic Cerebral HypoperfusionRGD 
Mapk14Ratcognitive disorder  ISOMapk14 (Mus musculus)associated with Chronic Cerebral HypoperfusionRGD 
Mapk14Mousecognitive disorder  IMP associated with Chronic Cerebral HypoperfusionRGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k5  (mitogen-activated protein kinase kinase kinase 5)
Mapk14  (mitogen activated protein kinase 14)

Genes (Mus musculus)
Map3k5  (mitogen-activated protein kinase kinase kinase 5)
Mapk14  (mitogen-activated protein kinase 14)

Genes (Homo sapiens)
MAP3K5  (mitogen-activated protein kinase kinase kinase 5)
MAPK14  (mitogen-activated protein kinase 14)


Additional Information