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 - 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 -