Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Lysosomal failure is central to neurodegenerative disorders, including Alzheimer's disease (AD).
• Down syndrome (DS), characterized by trisomy 21, is a neurodevelopmental disorder invariably leading to early-onset AD.
• The role of amyloid precursor protein (APP) in DS-associated lysosomal dysfunction remains incompletely understood.

Purpose of the Study:

• To investigate the specific mechanisms of lysosomal dysfunction in Down syndrome (DS).
• To determine the role of amyloid precursor protein (APP) and its fragments in DS pathogenesis.
• To explore therapeutic strategies for reversing lysosomal deficits in DS and AD.

Main Methods:

• Analysis of primary fibroblasts from individuals with DS and cortical neurons from Ts2 mouse models.
• Measurement of lysosomal pH, autophagic/endocytic substrate degradation, and cathepsin D activity.
• Intervention strategies including acidic nanoparticle delivery, siRNA-mediated APP knockdown, and BACE1 inhibition.

Main Results:

• DS cells exhibit impaired lysosomal degradation, elevated lysosomal pH, and reduced hydrolase activity, linked to the extra APP gene copy.
• Elevated APP-βCTF (C99) levels were identified as the specific mediator of lysosomal dysfunction.
• Correcting lysosomal pH with nanoparticles or reducing APP/APP-βCTF levels via siRNA or BACE1 inhibition reversed the observed deficits in cellular and animal models.

Conclusions:

• The extra APP gene copy in DS directly causes lysosomal acidification defects, leading to neurodegenerative pathology.
• APP-βCTF is a key pathogenic factor driving lysosomal failure in DS and potentially in sporadic AD.
• Targeting lysosomal pH and APP processing presents a promising therapeutic avenue for DS and AD.