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June 09, 2020; 94 (23) Article

Effect of ApoE isoforms on mitochondria in Alzheimer disease

Junxiang Yin, View ORCID ProfileEric M. Reiman, Thomas G. Beach, Geidy E. Serrano, Marwan N. Sabbagh, Megan Nielsen, Richard J. Caselli, View ORCID ProfileJiong Shi
First published May 26, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009582
Junxiang Yin
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.
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Eric M. Reiman
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.
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Thomas G. Beach
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.
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Geidy E. Serrano
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.
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Marwan N. Sabbagh
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.
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Megan Nielsen
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.
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Richard J. Caselli
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.
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Jiong Shi
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.
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  • ORCID record for Jiong Shi
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Effect of ApoE isoforms on mitochondria in Alzheimer disease
Junxiang Yin, Eric M. Reiman, Thomas G. Beach, Geidy E. Serrano, Marwan N. Sabbagh, Megan Nielsen, Richard J. Caselli, Jiong Shi
Neurology Jun 2020, 94 (23) e2404-e2411; DOI: 10.1212/WNL.0000000000009582

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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.

Glossary

AVLT-TL=
Auditory Verbal Learning Test total learning;
AD=
Alzheimer disease;
BNT=
Boston Naming Test;
CN=
cognitively normal;
CDR=
Clinical Dementia Rating;
DRS=
Dementia Rating Scale;
MTG=
middle temporal gyrus;
MCI=
mild cognitive impairment;
MMSE=
Mini-Mental State Examination;
SIRT3=
sirtuin 3

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 1009

  • Received August 13, 2019.
  • Accepted in final form December 26, 2019.
  • © 2020 American Academy of Neurology
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