Abstract
BACKGROUND
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.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
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This post is Copyright: | November 11, 2026
Neuro-Dementia