Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function.
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Williams C Andrew, Rose Shannon E, Stamenkovic Vera, Reid Aquene N, Travaglini Kyle J, Smith Stephen E P, Young Jessica E
Аннотация
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.
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.