Excess Collagen Accumulation in Microglia-Deficient Rats Mediated by Border-Associated Macrophages 2306686

Abstract Introduction There has been recent interest in investigating microglial dysfunction as a contributor to neurodegenerative conditions. Notably, recent studies have observed an accumulation of extracellular matrix (ECM) proteins in the brain of microglia-deficient rodents, potentially contributing to neurodegeneration by impairing removal of CNS waste products. The mechanism by which excess ECM deposits occur in the absence of microglia has not been elucidated. Recent work from the Pridans Lab at the University of Edinburgh has identified clusters of ECM-related and complement cascade proteins upregulated by border-associated macrophages (BAMs). This has led to the hypothesis that, in microglia absence, BAMs adopt microglial-like functions and overexpress ECM and complement cascade proteins resulting in excess ECM deposits. Methods This project intends to test this hypothesis by conducting immunoassays and histological analysis of collagen and complement proteins in brain tissue taken from microglia-deficient rats. FIRE-knockout rats will be used, which lack microglia but retain mostly unaffected BAM populations. Results Collagen deposition and complement protein expression is expected to increase in rats lacking microglia relative to wildtype controls. Conclusion This is the first study to explore microglia and collagen accumulation using a model that retains an almost normal BAM population. The results from this project may challenge the current consensus that microglia are solely responsible for maintaining ECM homeostasis, and propose BAM activity as a novel mechanism by which excess collagen accumulates in the CNS. Besides neurodegenerative diseases, this project may contribute to understanding the pathology of other conditions associated with dysfunctional microglia, including autism. The results could suggest a novel mechanism for these conditions and indicate future therapeutic targets. Funding Source Simons Institute for the Developing Brain (https://sidb.org.uk/) Topic Categories Neuroimmunology (NEUR)