In vivo validation of late-onset Alzheimer's disease genetic risk factors.
Alzheimers Dement
; 20(7): 4970-4984, 2024 07.
Article
em En
| MEDLINE
| ID: mdl-38687251
ABSTRACT
INTRODUCTION:
Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.METHODS:
Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.RESULTS:
We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes.DISCUSSION:
These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Camundongos Transgênicos
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Predisposição Genética para Doença
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Modelos Animais de Doenças
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Doença de Alzheimer
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Alzheimers Dement
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos