Abstract
INTRODUCTION
Synaptic dysfunction is an early feature of Alzheimer’s disease (AD) and proper localization of proteins involved in pre- and post-synaptic composition is dependent on endosomal recycling and trafficking, cellular processes involving the AD risk gene sortilin-related receptor 1 (SORL1).
METHODS
We examined SORL1’s role in synaptic protein composition and neuronal function in human excitatory cortical neurons. Synaptic protein interactions were analyzed using a mesoscale proteomics assay. Immunocytochemistry was used to visualize synaptic proteins and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits. Neuronal function was measured with multi-electrode arrays.
RESULTS
Loss of SORL1 expression significantly changes many synaptic protein–protein interactions and patterns of expression. SORL1-deficient neurons exhibit hyperactivity that is primarily amyloid beta independent. SORL1-deficient neurons also have impaired network plasticity.
DISCUSSION
These findings further support a growing body of literature implicating early endosomal recycling defects as drivers of AD pathogenesis.
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This post is Copyright: | September 22, 2026
Neuro-Dementia