Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease
- 1Columbia University
Abstract
MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. We test the hypothesis that an endosomal recycling pathway regulated by the interaction of SORL1 with retromer, which is pathogenically disrupted in AD, might drive the neurodegenerative process via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling AD's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, taken together with other findings, the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.
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BibTeX
@misc{qureshi2026disrupting,
title = {{Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease}},
author = {Y. H. Qureshi and J. Guo and J. H. Rinald and Z. Li and R. K. Soni and A. Govindarajan and E. Tortora and G. Uzunova and Y. Yang and S. Kannan and P. Nanayakkara and C. M. Troy and S. A. Small},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761980},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761980v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease
AU - Y. H. Qureshi
AU - J. Guo
AU - J. H. Rinald
AU - Z. Li
AU - R. K. Soni
AU - A. Govindarajan
AU - E. Tortora
AU - G. Uzunova
AU - Y. Yang
AU - S. Kannan
AU - P. Nanayakkara
AU - C. M. Troy
AU - S. A. Small
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761980
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761980v1
AB - MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. We test the hypothesis that an endosomal recycling pathway regulated by the interaction of SORL1 with retromer, which is pathogenically disrupted in AD, might drive the neurodegenerative process via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling AD's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, taken together with other findings, the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.
ER -