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The innate immunity protein IFITM3 modulates ?-secretase in Alzheimer's disease.

ABSTRACT: Innate immunity is associated with Alzheimer's disease¹, but the influence of immune activation on the production of amyloid-? is unknown^2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a ?-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-?. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to ?-secretase and upregulates its activity, thereby increasing the production of amyloid-?. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces ?-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 ?-secretase activity. The amount of IFITM3 in the ?-secretase complex has a strong and positive correlation with ?-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which ?-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

SUBMITTER: Hur JY

PROVIDER: S-EPMC7919141 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

Hur Ji-Yeun JY Frost Georgia R GR Wu Xianzhong X Crump Christina C Pan Si Jia SJ Wong Eitan E Barros Marilia M Li Thomas T Nie Pengju P Zhai Yujia Y Wang Jen Chyong JC Tcw Julia J Guo Lei L McKenzie Andrew A Ming Chen C Zhou Xianxiao X Wang Minghui M Sagi Yotam Y Renton Alan E AE Esposito Bianca T BT Kim Yong Y Sadleir Katherine R KR Trinh Ivy I Rissman Robert A RA Vassar Robert R Zhang Bin B Johnson Douglas S DS Masliah Eliezer E Greengard Paul P Goate Alison A Li Yue-Ming YM

Nature 20200902 7831

Innate immunity is associated with Alzheimer's disease<sup>1</sup>, but the influence of immune activation on the production of amyloid-β is unknown<sup>2,3</sup>. 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-β. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereb ...[more]

PMID: 32879487

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Project description:INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering A? production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP ?-site cleavage (equivalent to A?40), and Notch ?-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A? production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A? was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A? reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A? production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A? in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A? was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Dataset Information

The innate immunity protein IFITM3 modulates ?-secretase in Alzheimer's disease.

Publications

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

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