Abstract
INTRODUCTION
Interferon-induced transmembrane protein 3 (IFITM3) modulates γ-secretase in Alzheimer’s Disease (AD). Although IFITM3 knockout reduces amyloid β protein (Aβ) production, its cell-specific effect on AD remains unclear.
METHODS
Single nucleus RNA sequencing (snRNA-seq) was used to assess IFITM3 expression. Adeno-associated virus-BI30 (AAV-BI30) was injected to reduce IFITM3 expression in the cerebrovascular endothelial cells (CVECs). The effects on AD phenotypes in cells and AD mice were examined through behavioral tests, two-photon imaging, flow cytometry, Western blot, immunohistochemistry, and quantitative polymerase chain reaction assay (qPCR).
RESULTS
IFITM3 expression was increased in the CVECs of patients with AD. Overexpression of IFITM3 in primary endothelial cells enhanced Aβ generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ further increased IFITM3 expression, creating a vicious cycle. Knockdown of IFITM3 in CVECs decreased Aβ accumulation within cerebrovascular walls, reduced Alzheimer’s-related pathology, and improved cognitive performance in AD transgenic mice.
DISCUSSION
Knockdown of IFITM3 in CVECs alleviates AD pathology and cognitive impairment. Targeting cerebrovascular endothelial IFITM3 holds promise for AD treatment.
Highlights
Interferon-induced transmembrane protein 3 (IFITM3) expression was increased in the cerebrovascular endothelial cells (CVECs) of patients with Alzheimer’s Disease (AD).
Cerebrovascular endothelial IFITM3 regulates amyloid β protein (Aβ) generation through regulating beta-site APP cleaving enzyme 1 (BACE1) and γ-secretase.
Knockdown of IFITM3 in CVECs reduces Aβ deposits and improves cognitive impairments in AD transgenic mice.
Cerebrovascular endothelial IFITM3 could be a potential target for the treatment of AD.
If you do not see content above, kindly GO TO SOURCE.
Not all publishers encode content in a way that enables republishing at Neuro.vip.
This post is Copyright: Yijia Feng,
Shengya Wang,
Danlu Yang,
Wu Zheng,
Huwei Xia,
Qinxin Zhu,
Zhipeng Wang,
Bolang Hu,
Xinyi Jiang,
Xuemei Qin,
Chenkang Ni,
Wenhao Pan,
Yifan Zhao,
Sipei Pan,
Yun Zhang,
Weihong Song | January 14, 2025