TY - JOUR
T1 - Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids
AU - Zhao, Jing
AU - Lu, Wenyan
AU - Ren, Yingxue
AU - Fu, Yuan
AU - Martens, Yuka A.
AU - Shue, Francis
AU - Davis, Mary D.
AU - Wang, Xue
AU - Chen, Kai
AU - Li, Fuyao
AU - Liu, Chia Chen
AU - Graff-Radford, Neill R.
AU - Wszolek, Zbigniew K.
AU - Younkin, Steven G.
AU - Brafman, David A.
AU - Ertekin-Taner, Nilüfer
AU - Asmann, Yan W.
AU - Dickson, Dennis W.
AU - Xu, Ziying
AU - Pan, Meixia
AU - Han, Xianlin
AU - Kanekiyo, Takahisa
AU - Bu, Guojun
N1 - Funding Information:
This work was supported by NIH grants RF1AG051504, R37AG027924, RF1AG046205, RF1AG057181, P01NS074969, U19AG069701, U54NS110435, and P30AG062677 (to G.B.), a Cure Alzheimer’s Fund grant (to G.B), an Alzheimer’s Association Research Fellowship 2018-AARF-592302 (to J.Z.), NIH grants RF1AG071226 and RF1AG068034 (to T.K.), and NIH grant R01AG061796 (to N.E.-T.). This work was also partially supported by Mayo Clinic Center for Regenerative Medicine, Neuroregeneration Lab. Dr. Zbigniew K. Wszolek is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and by Albertson Parkinson's Research Foundation.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.
AB - APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.
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U2 - 10.1007/s00401-021-02361-9
DO - 10.1007/s00401-021-02361-9
M3 - Article
C2 - 34453582
AN - SCOPUS:85113766107
SN - 0001-6322
VL - 142
SP - 807
EP - 825
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 5
ER -