Metabolic brain diseaseJul 16, 2026

How Exercise May Protect the Brain in Alzheimer's Disease Through the CTSS Pathway

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 17, 2026

Abstract

Cathepsin S (CTSS) may serve as a biomarker for personalized exercise regimens in Alzheimer's disease.

CTSS is upregulated in Alzheimer's disease and is associated with neuroinflammation, blood-brain barrier dysfunction, and amyloid-beta dysregulation.
Exercise may protect against Alzheimer's disease by suppressing CTSS through anti-inflammatory, anti-aging, and metabolic pathways.
Myokines released during exercise and the elimination of senescent cells could inhibit the transcription of CTSS.
Activation of the AMPK-TFEB axis during exercise may enhance lysosomal function, reducing CTSS enzymatic activity.
Suppression of CTSS could help maintain blood-brain barrier integrity, reduce neuroinflammation, and improve amyloid-beta metabolism.

Simplified

Disease-modifying therapies for Alzheimer's disease (AD) targeting amyloid-β and tau have consistently failed, highlighting the urgent need for innovative therapeutic strategies. Cathepsin S (CTSS), a lysosomal cysteine protease upregulated in AD, functions as a "multifaceted disruptor" that interconnects neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ metabolic dysregulation. Although exercise is a validated non-pharmacological intervention that mitigates AD pathology, its multi-target molecular mechanisms remain elusive. Here, we propose and substantiate the "Exercise-CTSS-AD Axis" hypothesis, positing that exercise confers neuroprotection by suppressing CTSS through synergistic anti-inflammatory, anti-aging, and metabolic regulatory pathways. Exercise-induced myokines and clearance of senescent cells inhibit CTSS transcription, while AMPK-TFEB axis activation enhances lysosomal function to repress CTSS enzymatic activity. This systemic CTSS suppression preserves BBB integrity, ameliorates microglia-driven neuroinflammation, and restores Aβ homeostasis by reducing production and enhancing clearance. Our framework provides a unifying molecular explanation for the pleiotropic benefits of exercise, positions CTSS as a quantifiable biomarker for personalized exercise regimens, and supports an innovative combinatorial strategy: "Exercise + low-dose CTSS inhibitors" as a disease-modifying therapy for AD.

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How Exercise May Protect the Brain in Alzheimer's Disease Through the CTSS Pathway

Abstract

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