Project Summary There are currently no FDA-approved treatments for Alzheimer’s disease (AD) that target events that precede the loss of synaptic connectivity and cognitive decline. The cytoskeleton of neurons plays a crucial role in the development and maintenance of synaptic connections and dysregulation of the neuronal cytoskeleton is highly implicated in Alzheimer’s disease (AD). However, the order of early pathological events that drive cytotoxicity and neurodegeneration remain poorly understood. We recently discovered that depleting F-actin or inhibiting nonmuscle myosin 2 in neuronal processes caused dramatic changes to the microtubule cytoskeleton and dysregulated the transport of organelles in neuronal processes. This study revealed that disruption of actomyosin can cause neurodegenerative disease-linked phenotypes which have not been attributed to the actin cytoskeleton. Additionally, alterations to microtubules were completely reversed if actomyosin function was restored, indicating that the actin cytoskeleton is potentially a target to control microtubule-based processes and restore axonal defects. Based on our preliminary data, we hypothesize that dysregulation of actomyosin is an early event in AD that primes axons for degeneration and modifying its activity can mitigate AD-related pathology. The goal of this administrative supplement is to perform pilot studies to determine if neurons from Alzheimer’s disease mouse models have actomyosin defects and if they appear in an age-dependent manner. We will also modulate F-actin and myosin activity to investigate if the development of dystrophic neurites and axonal fragmentation caused by the application of Aβ oligomers can be reduced. This project, which is a natural extension of current work in the lab, will create a better understanding of the cellular events that cause AD and potentially identify new targets for therapeutic intervention.