2. Academic Validation
  3. Inclisiran attenuates Alzheimer's disease-like changes by suppressing microvascular endothelial ferroptosis to preserve blood-brain barrier integrity

Inclisiran attenuates Alzheimer's disease-like changes by suppressing microvascular endothelial ferroptosis to preserve blood-brain barrier integrity

  • Free Radic Biol Med. 2026 Mar 16:246:547-561. doi: 10.1016/j.freeradbiomed.2026.01.045.
Huayu Zhang 1,  Qian Xu 2,  Minghao Ye 3,  Xuanshuang Wu 4,  Zhong Ren 5,  Li Qin 6,  Zhihan Tang 7,  Guixue Wang 8,  Qiong Xiang 9,  Lushan Liu 10
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 2 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China; Department of Pathology, The Second Affiliated Hospital, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 3 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 4 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 5 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 6 JinFeng Laboratory, Chongqing, 401329, China; Ministry of Education Key Laboratory for Biorheological Science and Technology, National Local Joint Engineering Lab for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, 400044, China. Electronic address: [email protected].
  • 7 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 8 JinFeng Laboratory, Chongqing, 401329, China; Ministry of Education Key Laboratory for Biorheological Science and Technology, National Local Joint Engineering Lab for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, 400044, China. Electronic address: [email protected].
  • 9 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
  • 10 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province, 421001, China. Electronic address: [email protected].
PMID: 41605321 DOI: 10.1016/j.freeradbiomed.2026.01.045
Abstract

The integrity of blood-brain barrier (BBB) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ clearance and neurotoxic compound exclusion. Hyperlipidemia exacerbates AD by impairing the BBB function. Inclisiran, a PCSK9-targeting siRNA, reduces Cholesterol levels; however, its neuroprotective effects remain unclear. Here, we report the novel discovery that Inclisiran attenuates AD-like changes through the PCSK9-ferroptosis axis in brain microvascular endothelial cells (BMECs). First, integrated bioinformatics analysis and experimental validation of cortical tissues from patients with AD and healthy controls revealed a coordinated upregulation of PCSK9 and β-amyloid (Aβ), accompanied by increased iron deposition and significant activation of the Ferroptosis pathway. Interestingly, these changes are located in the BMECs of the blood-brain barrier rather than in the brain parenchyma. Second, in hyperlipidemic apoE-/- mouse models, integrated application of cerebral microvessel isolation, Molecular Biology techniques, immunofluorescence co-localization analysis, and behavioral tests demonstrated that Inclisiran significantly reduced AD-like changes by attenuating BBB dysfunction based on the suppression of PCSK9-mediated Ferroptosis in BMECs. Third, in vitro studies employing the HCMEC/D3 BBB model with integrated assessments of lipid peroxidation, mitochondrial function, and transwell-based barrier integrity demonstrated that Inclisiran significantly reduced Ferroptosis and restored BBB integrity via PCSK9 suppression. Our findings not only establish a novel PCSK9-ferroptosis-BBB regulatory axis in AD pathogenesis but also posit the clinically approved lipid-lowering drug, Inclisiran, as a promising therapeutic candidate for AD, providing new targets and mechanisms for the prevention and treatment of AD.

Keywords

Alzheimer's disease; Amyloid-beta; Blood–brain barrier; Ferroptosis; Inclisiran; Proprotein convertase subtilisin/kexin type 9.

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