The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.
Nature
; 586(7831): 735-740, 2020 10.
Article
en En
| MEDLINE
| ID: mdl-32879487
ABSTRACT
Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Unión al ARN
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Secretasas de la Proteína Precursora del Amiloide
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Enfermedad de Alzheimer
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Inmunidad Innata
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Proteínas de la Membrana
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Aged80
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Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2020
Tipo del documento:
Article