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Basic Science and Pathogenesis.

Jessica E Young1, Suman Jayadev1, Sonia B Sidhu2

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Summary
This summary is machine-generated.

Loss of SORL1 impairs microglial lysosomal function, leading to substrate accumulation and altered immune responses, potentially increasing Alzheimer's disease risk.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • The SORL1 gene encodes the sortilin related receptor protein SORLA, crucial for 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 expressed in brain microglia, and its deficiency causes enlarged lysosomes in derived cells.

Purpose of the Study:

  • To investigate the role of SORLA in microglial lysosomal function and its contribution to AD pathogenesis.
  • To elucidate how SORLA deficiency impacts lysosomal trafficking, degradation, and immune response in microglia.

Main Methods:

  • Generated SORL1 knockout (KO) human induced pluripotent stem cell-derived microglia-like cells (hMGLs) using CRISPR/Cas9.
  • Assessed lysosomal degradation, enzyme activity, substrate trafficking (HEXB, Cathepsin B/D), lysosomal exocytosis, and accumulation of amyloid-beta (Aß) and synaptosomes.
  • Evaluated phagocytosis and inflammatory responses in SORL1 KO hMGLs.

Main Results:

  • SORLA deficiency led to decreased lysosomal degradation and enzyme activity due to impaired lysosomal enzyme trafficking in hMGLs.
  • Phagocytosis of Aß (1-42) and synaptosomes increased, but aberrant accumulation occurred due to reduced degradation.
  • Lysosomal exocytosis was impaired in SORL1-deficient microglia, potentially altering immune responses.

Conclusions:

  • SORLA plays a critical role in microglial lysosomal hydrolase trafficking, essential for microglial function.
  • The microglial endo-lysosomal network is a potential pathway for SORL1 in AD risk and pathogenesis.
  • Findings may guide the development of novel therapeutic targets for AD focusing on lysosomes and microglia.