Abstract
INTRODUCTION
SORL1 encodes the sorting receptor SORLA, a major genetic contributor to Alzheimer’s disease (AD). Although SORL1 loss disrupts endosomal trafficking and promotes amyloidogenic amyloid precursor protein (APP) processing, the functional consequences of specific missense variants in human neurons remain unclear.
METHODS
We used isogenic induced pluripotent stem cell (iPSC)-derived NGN2 neurons and 3D cerebral organoids carrying wild-type, SORL1 p.Y1816C knock-in, or SORL1 knockout alleles. We analyzed SORLA maturation and shedding, APP localization, amyloid-β (Aβ) secretion, endosomal morphology, axonal transport of Rab5+ endosomes and APP, and network activity.
RESULTS
The p.Y1816C variant impaired SORLA maturation and shedding and, together with knockout, caused enlarged early endosomes, APP retention, elevated Aβ secretion, amyloid deposition in organoids, axonal swellings, disrupted axonal transport, and neuronal hyperexcitability.
CONCLUSIONS
The SORL1 p.Y1816C variant is pathogenic in human neurons, and we reveal novel roles for SORLA in axonal transport and neuronal excitability. These findings highlight endosomal trafficking disruption as a central mechanism in AD pathogenesis.
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This post is Copyright: | August 22, 2026
Neuro-Dementia