Minghui Wang, United States of America
Icahn School of Medicine at Mount Sinai Genetics and Genomic SciencesAuthor Of 1 Presentation
THE INNATE IMMUNITY PROTEIN IFITM3 MODULATES GAMMA-SECRETASE IN ALZHEIMER’S DISEASE
Abstract
Aims
Innate immunity is associated with Alzheimer’s disease, but the influence of immune activation on the production of amyloid-beta is unknown.
Methods
We used photolableing using a GSM followed by mass spectrometry to identify gamma-secretase modulatory proteins.We used aging mouse brains, 5xFAD alzheimer transgenic mice, primary neurons, astrocytes, and late-onset human brains to investigate the effect of the innate immunity protein IFITM3 on gamma-secretase and its activity.
Results
We identify interferon-induced transmembrane protein 3 (IFITM3) as a gamma-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-beta. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to gamma-secretase and upregulates its activity, thereby increasing the production of amyloid-beta. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer’s disease genes. Furthermore, knockout of IFITM3 reduces gamma-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 gamma-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with gamma-secretase activity in samples from patients with late-onset Alzheimer’s disease.
Conclusions
These findings reveal a mechanism in which gamma-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer’s disease is thereby increased.