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Depletion of the AD risk gene SORL1 selectively impairs neuronal endosomal traffic independent of amyloidogenic APP processing
Author(s) -
Knupp Allison,
Mishra Swati,
Martinez Refugio A.,
Braggin Jacquelyn E.,
Small Scott A.,
Jayadev Suman,
Young Jessica E.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.037222
Subject(s) - endosome , biology , amyloid precursor protein , microbiology and biotechnology , endocytic cycle , microglia , neuroscience , endocytosis , alzheimer's disease , genetics , immunology , cell , medicine , disease , pathology , intracellular , inflammation
Background The SORL1 gene encodes for the protein SorLA, a sorting receptor involved in retromer‐related endosomal traffic. Many SORL1 genetic variants increase Alzheimer’s disease (AD) risk, and rare loss‐of‐function truncation mutations have been found to be causal of AD. SORL1 is expressed in neurons and glia of the central nervous system and loss of SORL1 has been reported AD tissue. Method To model the causal loss‐of‐function mutations, we used CRISPR/Cas9 technology to deplete SORL1 in human induced pluripotent stem cells (hiPSCs) to test the hypothesis that loss of SORL1 contributes to AD pathogenesis by leading to endosome dysfunction. Result We report that loss of SORL1 in hiPSC‐derived neurons leads to early endosome enlargement, a cellular phenotype that is indicative of ‘traffic jams’ and is now considered a hallmark cytopathology AD. We validate defects in neuronal endosomal traffic by showing decreased localization of amyloid‐precursor protein (APP) in the trans‐Golgi network (TGN), and increased localization of APP in early endosomes, a site of APP cleavage by the b secretase BACE1. Microglia, immune cells of the CNS, which also play a role in the AD pathology also express SORL1 . We therefore tested and found no effect of SORL1 depletion on endosome size or morphology in hiPSC‐derived microglia, suggesting a selective effect on neuronal endocytic trafficking. Finally, because BACE1 dependent APP fragments can cause endosome enlargement, we treated SORL1 deficient hiPSC‐derived neurons with BACE1 inhibitors and demonstrate that endosome enlargement occurs independent of amyloidogenic APP fragments. Conclusion Collectively, these findings clarify where and how SORL1 links to AD. Moreover, our data, together with recent findings, underscores how sporadic AD pathways that regulate endosomal trafficking, and autosomal‐dominant AD pathways that regulate APP cleavage, independently converge on AD’s defining cytopathology.