BETA AMYLOID-INDUCED DYSREGULATION OF THE EXOCYST COMPLEX IMPEDES POSTSYNAPTIC RECEPTOR TRAFFICKING AND ALTERS DENDRITIC SPINES

Abstract

Synaptic dysfunction and loss are hallmarks of the early pathogenesis of Alzheimer’s disease (AD), leading to impaired cognitive function, including disruption of memory processing. Accumulation of neurotoxic oligomeric beta amyloid (Aβ) in the prodromic period leading up to AD is thought to contribute to dendrite atrophy, altered dendritic spine dynamics resulting in synaptic dysfunction and spine loss, and compromised postsynaptic receptor trafficking, but the molecular mechanisms for these Aβ-associated changes are still yet to be fully understood. As the exocyst complex has been implicated in vesicle tethering and trafficking preceding SNARE protein-mediated vesicle exocytosis in yeast and mammalian cells, and preliminary work in our laboratories has found evidence of exocyst involvement in amyloid precursor protein (APP) trafficking in murine primary neurons, I investigated the impact of neurotoxic levels of Aβ on the octameric exocyst complex in relation to altered dendrite and spine integrity and postsynaptic receptor trafficking in spines. Specifically, I utilized Actin-GFP expression to examine dendritic arborization as a measure of neuronal complexity and dendritic spine dynamics, which are driven by cytoskeletal changes, and immunocytochemistry and proximity ligand assay (PLA) of key exocyst subunits and AMPA GluA1 receptors in conjunction with select exocyst subunit deletion to correlate Aβ -induced changes in the exocyst with altered postsynaptic receptor trafficking. The results were consistent with our central hypothesis that Aβ induces dysregulation of the exocyst complex, obstructing major postsynaptic neurotransmitter receptor AMPAR trafficking and, consequently, contributing to neurodegeneration through dendrite atrophy and loss of dendritic spine density in AD. The findings provide new insights into the molecular mechanisms underlying synapse dysfunction in AD pathogenesis, potentially revealing novel targets for therapeutic intervention.