The Alzheimer's disease gene SORL1 regulates lysosome function in human microglia

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• The SORL1 gene encodes the SORLA protein, a key regulator of endo-lysosomal trafficking.
• Loss-of-function variants in SORL1 are linked to Alzheimer's disease (AD), with reduced SORLA expression observed in AD brains.
• SORLA is highly expressed in brain microglia, the resident immune cells.

Purpose of the Study:

• To investigate how SORLA deficiency impacts lysosomal function in microglia.
• To elucidate the role of microglial lysosomal dysfunction in AD pathogenesis.
• To explore SORLA's contribution to AD risk via microglial pathways.

Main Methods:

• Utilized human induced pluripotent stem cell-derived microglia-like cells (hMGLs).
• Assessed lysosomal degradation, enzyme activity, and substrate trafficking in SORLA-deficient hMGLs.
• Examined phagocytosis of amyloid-beta and synaptosomes, and lysosomal exocytosis.

Main Results:

• SORLA deficiency led to impaired lysosomal degradation and reduced lysosomal enzyme activity in hMGLs.
• Amyloid-beta and synaptosomes were phagocytosed but accumulated abnormally due to impaired degradation.
• Lysosomal exocytosis was impaired in SORLA-deficient microglia, potentially altering immune responses.

Conclusions:

• SORLA is crucial for proper lysosomal hydrolase trafficking and microglial function.
• The microglial endo-lysosomal network represents a novel pathway for SORL1 in AD risk.
• Findings suggest potential therapeutic targets related to lysosomes and microglia for AD treatment.