Junxiang Yin1, Eric M Reiman1, Thomas G Beach1, Geidy E Serrano1, Marwan N Sabbagh1, Megan Nielsen1, Richard J Caselli1, Jiong Shi2. 1. From the Barrow Neurological Institute (J.Y., M.N.S., M.N., J.S.), St. Joseph Hospital and Medical Center, Phoenix, AZ; Banner Alzheimer's Institute (E.M.R.), Phoenix, AZ; Civin Laboratory for Neuropathology (T.G.B., G.E.S.), Banner Sun Health Research Institute, Sun City, AZ; Cleveland Clinic Lou Ruvo Center for Brain Health (M.N.S.), Las Vegas, NV; School of Life Sciences (M.N.), Arizona State University, Tempe; Department of Neurology (R.J.C.), Mayo Clinic Arizona, Scottsdale; Advanced Innovation Center for Human Brain Protection (J.S.), Capital Medical University, Beijing, China; and China National Clinical Research Center for Neurological Diseases (J.S.), Beijing Tiantan Hospital, Capital Medical University, Beijing. 2. From the Barrow Neurological Institute (J.Y., M.N.S., M.N., J.S.), St. Joseph Hospital and Medical Center, Phoenix, AZ; Banner Alzheimer's Institute (E.M.R.), Phoenix, AZ; Civin Laboratory for Neuropathology (T.G.B., G.E.S.), Banner Sun Health Research Institute, Sun City, AZ; Cleveland Clinic Lou Ruvo Center for Brain Health (M.N.S.), Las Vegas, NV; School of Life Sciences (M.N.), Arizona State University, Tempe; Department of Neurology (R.J.C.), Mayo Clinic Arizona, Scottsdale; Advanced Innovation Center for Human Brain Protection (J.S.), Capital Medical University, Beijing, China; and China National Clinical Research Center for Neurological Diseases (J.S.), Beijing Tiantan Hospital, Capital Medical University, Beijing. jshi2000@yahoo.com.
Abstract
OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD. METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25). RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance. CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.
OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD. METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25). RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance. CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.
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