title: Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice.
abstract: Alzheimer'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 (Aβ)1-40 or 1-42 levels in 5xFAD mice. In addition, the glucose- and oxygen-deprivation-induced apoptotic neuronal death in Aβ-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.
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, The People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Esha
authors.initials: E
authors.lastname: Gauba
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, The People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Neha
authors.initials: N
authors.lastname: Tandon
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Malini
authors.initials: M
authors.lastname: Shankar
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Beck
authors.affiliation: Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, The People's Republic of China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.|Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, The People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Du
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress
chemical_list: D016229:Amyloid beta-Peptides