The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function
C. Andrew Williams, Shannon E. Rose, Vera Stamenkovic, Aquene N. Reid, Kyle J. Travaglini, Stephen E. P. Smith, Jessica E. YoungAbstract
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.