The Role of Microglia in the Etiology and Evolution of Chronic Traumatic Encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that presents as a late sequela from traumatic brain injury (TBI). TBI is a growing and under-recognized public health concern with a high degree of morbidity and large associated global costs. While the immune response to TBI is complex, its contribution to the development of CTE remains largely unknown. In this review, we summarize the current understanding of the link between CTE and the resident innate immune system of the brain-microglia. We discuss the neuropathology underlying CTE including the creation and aggregation of phosphorylated tau protein into neurofibrillary tangles and the formation of amyloid beta deposits. We also present how microglia, the resident innate immune cells of the brain, drive the continuous low-level inflammation associated with the insidious onset of CTE. In this review, we conclude that the latency period between the index brain injury and the long-term development of CTE presents an opportunity for therapeutic intervention. Encouraging advances with microtubule stabilizers, cis p-tau antibodies, and the ability to therapeutically alter the inflammatory state of microglia have shown positive results in both animal and human trials. Looking forward, recent advancements in next-generation sequencing technology for the study of genomic, transcriptomic, and epigenetic information will provide an opportunity for significant advancement in our understanding of prorepair and pro-injury gene signatures allowing for targeted intervention in this highly morbid injury process.

Figure 1. Schematic of microglial priming

A) Standard rodent traumatic brain injury induced via controlled cortical impact. B) Traumatic brain injury generates a priming effect within microglia driving a chronic low-level inflammatory environment over time. This chronic inflammation leads to both an increased susceptibility to secondary injury as well as the long-term development of chronic traumatic encephalopathy.

Figure 2. Schematic of physiologic and pathophysiologic microglial activation

Under conditions of homeostasis microglia continually survey the local microenvironment for invading pathogens and cellular debris. Perturbations within this environment, such as traumatic injury, result in activation of microglia. Activated microglia release a myriad of inflammatory mediators to aid in the clearance of necrotic debris and amyloid beta plaques generated during the injury process. Activated microglia are also capable of limiting tau phosphorylation (p-tau) and the subsequent development of p-tau oligomers. If the inflammation fails to completely resolve, as is often the case with severe injury or repetitive injury, microglia can assume a pathophysiologic state of chronic activation. Chronically activated microglia are unable to clear amyloid beta, allow association of p-tau into oligomers and neurofibrillary tangles (NFT), and generate an exaggerated response to subsequent traumatic or inflammatory stimuli all of which lead to the subsequent development of chronic traumatic encephalopathy.