Microglial Roles in Alzheimer's Disease: An Agent ‐Based Model to Elucidate Microglial Spatiotemporal Response to Beta‐Amyloid

AbstractAlzheimer's Disease (AD) is characterized by beta-amyloid (A β) 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 sta te and form barriers around plaques. We seek 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 an agent-based model (ABM) to characterize the spatiotemporal interactions between microglia and Aβ. 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,in silico behavioral knock-out simulations show that phagocytosis knock-outs have the strongest impact on plaque size, but modest impacts on microglial coverage and activation. In contrast, the chemotaxis knock-outs had a strong impact on microglial coverage with a more modest impact on plaque volume and microglial activa...
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Tags: ARTICLE Source Type: research