Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's-related phenotypes

  • Alzheimers Dement. 2025 Feb;21(2):e14543. doi: 10.1002/alz.14543.
Yijia Feng  1 ,  Shengya Wang  1 ,  Danlu Yang  1 ,  Wu Zheng  2 ,  Huwei Xia  1 ,  Qinxin Zhu  1 ,  Zhipeng Wang  1 ,  Bolang Hu  1 ,  Xinyi Jiang  1 ,  Xuemei Qin  1 ,  Chenkang Ni  1 ,  Wenhao Pan  1 ,  Yifan Zhao  1 ,  Sipei Pan  1  3 ,  Yun Zhang  4 ,  Weihong Song  1  3
Affiliations
  • 1. Center for Geriatric Medicine, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The First Affiliated Hospital and Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Neuroscience Medical Center, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China.
  • 3. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, China.
  • 4. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
PMID: 39807629 DOI: 10.1002/alz.14543
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.

Keywords
Alzheimer's Disease; Aβ; IFITM3; cerebrovascular endothelium; cognitive impairment.
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