APOE ε4-dependent effects on the early amyloid pathology in induced neurons of patients with Alzheimer’s disease
Abstract Background The ε4 allele of apolipoprotein E ( APOE ε4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid...
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Published in | Translational neurodegeneration Vol. 11; no. 1; pp. 1 - 45 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
London
BioMed Central
25.10.2022
BMC |
Subjects | |
Online Access | Get full text |
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Summary: | Abstract
Background
The ε4 allele of apolipoprotein E (
APOE
ε4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), associated with amyloid pathogenesis. However, it is not clear how
APOE
ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid development in AD patient neurons.
Methods
AD patient induced neurons (iNs) with an
APOE
ε4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing
APOE
ε4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the
APOE
ε4-mediated amyloidosis.
Results
We optimized amyloid seeding stage in the iNs of AD patients that transiently expressed
APOE
ε4. Remarkably, we demonstrated that Aβ pathology was aggravated by the induction of
APOE
ε4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of
APOE
ε4-associated AD.
Conclusions
Our findings suggest that the presence of
APOE
ε4 at the early Aβ-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of
APOE
ε4 expression for the progression and pathogenesis of sporadic AD. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2047-9158 2047-9158 |
DOI: | 10.1186/s40035-022-00319-9 |