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Sci Transl Med. 2020 Feb 5;12(529). pii: eaay1809. doi: 10.1126/scitranslmed.aay1809.

APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
2
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA.
3
Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA.
4
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. bu.guojun@mayo.edu.

Abstract

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by driving amyloidpathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson's disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.

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