Weathered Agent-Based Model of Microglia-Plaque Interactions

<p>Alzheimer’s Disease (AD) is characterized by beta-amyloid (Aβ) plaques in the brain and widespread neuronal damage. Due to high drug attrition rates in AD, there is increased interest in characterizing neuroimmune responses to Aβ plaques. In response to AD pathology, microglia are innate phagocytotic immune cells which transition into a neuroprotective state and form barriers around plaques.</p>

<p>This model seeks to understand the role of microglia in modifying Aβ dynamics and barrier formation. To quantify the influence of individual microglia behaviors (activation, chemotaxis, phagocytosis, and proliferation) on plaque size and barrier coverage, we developed this agent-based model (ABM) to characterize the spatiotemporal interactions between microglia and Aβ.</p>

<p>Our model qualitatively reproduces mouse data trends reported in Condello et al. 2015, where the fraction of microglia coverage decreases as plaques become larger. In our model, the time to microglial arrival at the plaque boundary is significantly negatively correlated (p<0.0001) with plaque size, indicating the importance of the time to microglial activation for regulating plaque size. Additionally, <em>in silico</em> behavioral knock-out simulations show a significant increase (p<0.0001) in plaque size with knocked out microglial activation, chemotaxis, or phagocytosis. The phagocytosis knockout showed a significant increase in a functionally activated microglia and plaque size, leading to a decrease in overall coverage. These simulations suggest that targeting microglial activation, phagocytosis, and chemotaxis could be a viable pharmacological strategy for the treatment of AD. </p>