2. Academic Validation
  3. Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's-related phenotypes

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

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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