Targeting peripheral cathepsin E restricts CD8⁺ T-cell neuroinvasion and ameliorates Alzheimer's disease pathology.

Authors

Zhen Xie, Qinghu Yang, Lijuan Liu, Min Chu, Zhenzhen Quan, Liang Yang, Zhantao Bai, Ke Yang, Hiroshi Nakanishi, Liyong Wu, Hong Qing, Junjun Ni

Published in

Alzheimer's & dementia : the journal of the Alzheimer's Association. Volume 22. Issue 11.

Abstract

CD8⁺ T-cell-mediated neuroimmune activation increases with aging and contributes to Alzheimer's disease (AD), yet the molecular cues that drive their recruitment into the brain remain largely undefined.
We quantified Cathepsin E (CatE) expression in CD8⁺ T cells from 5×FAD mice and clinical samples from patients with AD. The functional necessity of CatE in T-cell trafficking was assessed through 4D-data-independent acquisition (4D-DIA) proteomics, microfluidic migration assays under physiological flow, and adoptive transfer experiments. Finally, we evaluated the therapeutic efficacy of a brain-impermeable CatE inhibitor in mitigating AD-related pathology.
CatE is selectively and age-dependently upregulated in peripheral CD8⁺ T cells in both AD mice and patients. Adoptive transfer of AD-derived CD8⁺ T cells significantly accelerated promoted soluble Aβ₁_{- 4 2} accumulation, glial activation, and memory deficits in 5-month-old recipient mice. Mechanistically, CatE is associated with elevated expression of vinculin and fibronectin in CD8⁺ T cells, accompanied by enhanced activation of β1-integrins that stabilizes adhesion to brain endothelial cells. Pharmacological suppression of peripheral CatE effectively restricted T-cell infiltration, attenuated neuroinflammation, and restored cognitive function in AD models.
These results identify CatE as a key cell-intrinsic regulator of CD8⁺ T-cell migratory competence. Targeting the peripheral CatE-integrin axis offers a promising immunotherapeutic strategy to limit pathogenic neuroinflammation in AD while circumventing the challenges of blood-brain barrier penetration.

PMID:
43015247
Bibliographic data and abstract were imported from PubMed on 12 Nov 2026.

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