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

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Alzheimer disease (AD) is linked to abnormal amyloid precursor protein (APP) processing and impaired lysosomal function.
• Lysosomal dysfunction contributes to neuroinflammation and neurodegeneration in AD.

Purpose of the Study:

• To investigate the role of lysosomal multi-enzyme complex (LMC) members, neuraminidase 1 (Neu1) and protective protein/cathepsin A (PPCA), in APP metabolism.
• To explore the therapeutic potential of targeting the Neu1-PPCA axis in AD.

Main Methods:

• Analysis of human AD brains and 5xFAD/Neu1-/- mouse models.
• Investigating the impact of Neu1 deficiency and PPCA/Neu1 co-expression on APP processing and lysosomal function.
• Utilizing AAV-mediated gene delivery in 5XFAD mouse brains.

Main Results:

• Neu1 deficiency causes sialic acid retention on APP and secretases, increasing amyloidogenic cleavage and Aβ42 production.
• Neu1 deficiency promotes lysosomal exocytosis, leading to extracellular Aβ release and neuroinflammation.
• PPCA overexpression or Neu1-PPCA co-expression normalizes sialylation, reduces secretase activity, and mitigates amyloid plaque burden.

Conclusions:

• Neu1 and PPCA form a critical axis regulating APP metabolism and lysosomal homeostasis.
• The Neu1-PPCA axis represents a novel therapeutic target for Alzheimer disease.
• AAV-mediated co-expression of Neu1 and PPCA shows promise in reducing AD pathology.