TY - JOUR
T1 - Effect of ApoE isoforms on mitochondria in Alzheimer disease
AU - Yin, Junxiang
AU - Reiman, Eric M.
AU - Beach, Thomas G.
AU - Serrano, Geidy E.
AU - Sabbagh, Marwan N.
AU - Nielsen, Megan
AU - Caselli, Richard J.
AU - Shi, Jiong
N1 - Funding Information:
J. Yin is funded by the Flinn Foundation (2190) and the Barrow Neurological Foundation (3032226). E.M. Reiman is funded by NIH grant P30AG19610 (Arizona Alzheimer's Disease Core Center), R01AG055444, and R01AG031581. T.G. Beach and G.E. Serrano are funded by NIH grant P30AG19610 (Core D: Neuropathology Core) and the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders). M.N. Sabbagh is funded by R01AG059008. M. Nielsen is funded by the Barrow Neurological Foundation (3032226). R.J. Caselli is funded by NIH grant P30AG19610 (Core B: Clinical Core) and R01AG031581. J. Shi is funded by the Flinn Foundation (2190) and the Barrow Neurological Foundation (3032226). Go to Neurology.org/N for full disclosures.
Funding Information:
This work is funded by the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Flinn Foundation (2190), and the Barrow Neurological Foundation (3032226). In addition, the Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders).
Publisher Copyright:
© American Academy of Neurology.
PY - 2020/6/9
Y1 - 2020/6/9
N2 - ObjectiveTo 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.MethodsWe 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-ϵ4 carriers (n = 21) and noncarriers (n = 25).ResultsLevels of these proteins were compared between ApoE-ϵ4 carriers and noncarriers. ApoE-ϵ4 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.ConclusionApoE 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-ϵ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.
AB - ObjectiveTo 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.MethodsWe 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-ϵ4 carriers (n = 21) and noncarriers (n = 25).ResultsLevels of these proteins were compared between ApoE-ϵ4 carriers and noncarriers. ApoE-ϵ4 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.ConclusionApoE 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-ϵ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.
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U2 - 10.1212/WNL.0000000000009582
DO - 10.1212/WNL.0000000000009582
M3 - Article
C2 - 32457210
AN - SCOPUS:85086283513
SN - 0028-3878
VL - 94
SP - E2404-E2411
JO - Neurology
JF - Neurology
IS - 23
ER -