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Basic Science and Pathogenesis.

Brooke A DeRosa1, Yalun Zhang2, Charles G Golightly1

  • 1John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

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|December 24, 2025
PubMed
Summary
This summary is machine-generated.

A SORL1 gene deletion disrupts endolysosomal trafficking in Alzheimer's disease (AD) models, impacting amyloid precursor protein (APP) processing and microglial function. This suggests SORL1's critical role in AD pathogenesis.

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Endolysosomal trafficking disruptions are central to Alzheimer's disease (AD) pathogenesis.
  • The SORL1 gene is a significant risk factor for AD, encoding a receptor crucial for endosomal trafficking of amyloid precursor protein (APP) and amyloid-beta (Aβ).

Purpose of the Study:

  • To investigate the impact of a protein-truncating SORL1 variant (C1431fs) on endolysosomal trafficking and APP processing in Alzheimer's disease models.
  • To assess the cellular and molecular consequences of the SORL1 C1431fs deletion in neuronal and microglial cells.

Main Methods:

  • Generated induced pluripotent stem cell (iPSC) lines from AD patients with a SORL1 C1431fs deletion and created isogenic controls using CRISPR/Cas9.
  • Differentiated iPSCs into forebrain neurons and microglia to study endolysosomal trafficking and APP processing.
  • Utilized HEK293-APPswe cells overexpressing wild-type or variant SORL1 for comparative analysis.

Main Results:

  • The SORL1 C1431fs variant increased secretion of Aβ42, Aβ40, sAPPα, and sAPPβ in HEK293 cells.
  • In neurons, the SORL1 deletion caused APP accumulation in early endosomes, endosomal swelling, and increased early endosome numbers.
  • Microglial phagocytic activity for Aβ42 was reduced by the SORL1 deletion, with ongoing studies on cytokine secretion.

Conclusions:

  • The SORL1 C1431fs deletion induces endolysosomal trafficking defects in both neurons and microglia.
  • These findings highlight SORL1's multifaceted role in AD pathogenesis, affecting neuronal APP processing and microglial immune responses.