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bioRxiv · 10.1101/2025.04.28.651121

Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model

Fremuth, L. E.·van de Vlekkert, D.·Hu, H.·Weesner, J. A.·Annunziata, I.·d'Azzo, A.
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Abstract

Alzheimer disease (AD) is characterized by aberrant amyloid precursor protein (APP) processing and lysosomal dysfunction. This study identifies two members of the lysosomal multi-enzyme complex (LMC), neuraminidase 1 (Neu1) and protective protein/cathepsin A (PPCA), as a critical regulators of APP metabolism. Neu1 deficiency in human AD brains and 5xFAD/Neu1-/- mice leads to sialic acid retention on APP and its secretases, enhancing amyloidogenic cleavage and A{beta}42 production. Additionally, Neu1 deficiency increases lysosomal exocytosis, contributing to extracellular A{beta} release and neuroinflammation. Conversely, overexpression of PPCA in neurons or co-expression of PPCA and NEU1 normalizes sialylation patterns, reduces secretase activity, and mitigates plaque burden. These findings reveal a novel bidirectional dependency between Neu1 and PPCA, underscoring their cooperative role in maintaining lysosomal homeostasis. Additionally, AAV-mediated co-expression of NEU1 and PPCA in 5XFAD brains demonstrates therapeutic potential by reducing amyloid pathology. These findings position lysosomal dysfunction and the Neu1-PPCA axis as promising targets for therapeutic intervention in AD.

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Fremuth, L. E., van de Vlekkert, D., Hu, H., Weesner, J. A., Annunziata, I., d'Azzo, A.. 2025-05-02. Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model. https://doi.org/10.1101/2025.04.28.651121

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