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

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 Aβ42 production. Additionally, Neu1 deficiency increases lysosomal exocytosis, contributing to extracellular Aβ 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. Competing Interest Statement The authors have declared no competing interest. Footnotes We have added an author, Dr. Gouri Yogalingam, who was previously not included. Dr. Yogalingam is responsible for generating the PPCA overexpression mouse lines that were used heavily throughout this manuscript.