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APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid
- Source :
- Sci Transl Med
- Publication Year :
- 2019
-
Abstract
- The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology is not clear. Here we generated a mouse model of synucleinopathy using an adeno-associated virus (AAV) gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3 or APOEE4. 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 nine 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 demonstrates a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.
- Subjects :
- Apolipoprotein E
Lewy Body Disease
Pathology
medicine.medical_specialty
Synucleinopathies
Mice, Knockout, ApoE
Apolipoprotein E4
Disease
Article
Transcriptome
Mice
mental disorders
medicine
Dementia
Animals
Allele
Amyloid beta-Peptides
Lewy body
business.industry
Dementia with Lewy bodies
General Medicine
medicine.disease
Astrogliosis
nervous system diseases
alpha-Synuclein
lipids (amino acids, peptides, and proteins)
business
human activities
Subjects
Details
- ISSN :
- 19466242
- Volume :
- 12
- Issue :
- 529
- Database :
- OpenAIRE
- Journal :
- Science translational medicine
- Accession number :
- edsair.doi.dedup.....d62676212be5002c8a8702f5c6ae0bc0