Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice

dc.contributor.authorLu, Linen_US
dc.contributor.authorGuo, Lanen_US
dc.contributor.authorGauba, Eshaen_US
dc.contributor.authorTian, Jingen_US
dc.contributor.authorWang, Luen_US
dc.contributor.authorTandon, Nehaen_US
dc.contributor.authorShankar, Malinien_US
dc.contributor.authorBeck, Simon J.en_US
dc.contributor.authorDu, Yifengen_US
dc.contributor.authorDu, Hengen_US
dc.contributor.utdAuthorLu, Linen_US
dc.contributor.utdAuthorGuo, Lanen_US
dc.contributor.utdAuthorGauba, Eshaen_US
dc.contributor.utdAuthorTian, Jingen_US
dc.contributor.utdAuthorWang, Luen_US
dc.contributor.utdAuthorTandon, Nehaen_US
dc.contributor.utdAuthorShankar, Malinien_US
dc.contributor.utdAuthorBeck, Simon J.en_US
dc.contributor.utdAuthorDu, Hengen_US
dc.description.abstractAlzheimer's disease (AD) is heterogeneous and multifactorial neurological disorder; and the risk factors of AD still remain elusive. Recent studies have highlighted the role of vascular factors in promoting the progression of AD and have suggested that ischemic events increase the incidence of AD. However, the detailed mechanisms linking ischemic insult to the progression of AD is still largely undetermined. In this study, we have established a transient cerebral ischemia model on young 5xFAD mice and their non-transgenic (nonTg) littermates by the transient occlusion of bilateral common carotid arteries. We have found that transient cerebral ischemia significantly exacerbates brain mitochondrial dysfunction including mitochondrial respiration deficits, oxidative stress as well as suppressed levels of mitochondrial fusion proteins including optic atrophy 1 (OPA1) and mitofusin 2 (MFN2) in young 5xFAD mice resulting in aggravated spatial learning and memory. Intriguingly, transient cerebral ischemia did not induce elevation in the levels of cortical or mitochondrial Amyloid beta (Aß)1-40 or 1-42 levels in 5xFAD mice. In addition, the glucose- and oxygen-deprivation-induced apoptotic neuronal death in Aß-treated neurons was significantly mitigated by mitochondria-targeted antioxidant mitotempo which suppresses mitochondrial superoxide levels. Therefore, the simplest interpretation of our results is that young 5xFAD mice with pre-existing AD-like mitochondrial dysfunction are more susceptible to the effects of transient cerebral ischemia; and ischemic events may exacerbate dementia and worsen the outcome of AD patients by exacerbating mitochondrial dysfunction.;en_US
dc.description.sponsorshipThis study was supported by National Institute on Aging (R00AG037716), Alzheimer's Association (NIRG-12-242803), National Science Foundation of China (131271145, 1381200847), and National Science Foundation of Shandong (2013JQB14007).en_US
dc.identifier.bibliographicCitationLu, Lin, Lan Guo, Esha Gauba, Jing Tian, et al. 2015. "Transient cerebral ischemia promotes brain mitochondrial dysfunction and exacerbates cognitive impairments in young 5xFAD mice." PLOS One 10(12), doi: 10.1371/journal.pone.0144068en_US
dc.publisherPublic Library of Scienceen_US
dc.rightsCC BY 4.0 (Attribution)en_US
dc.rights©2015 The Authorsen_US
dc.sourcePLOS One
dc.subjectCerebral ischemiaen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectTransgenic miceen_US
dc.subjectTransient ischemic attacken_US
dc.titleTransient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Miceen_US


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