Fig. 4
Proposed cellular mechanisms of tau phosphorylation in TBI and CTE. a Traumatic brain injury (TBI) is characterized by an initial primary injury response, in which increased mechanical forces and strain lead to axonal shearing and blood–brain barrier disruption. In response, innate and peripheral immune cells migrate to the damaged region where they sense disease-associated molecular patterns (DAMPs) and facilitate tissue healing mechanisms. b Microglia and astrocytes respond to DAMPs released from dystrophic neurons and become activated accordingly. Microglia take on a pro- or anti-inflammatory molecular signature characterized by the release of various cytokines and the expression of certain receptors. Activation of the complement cascade and NLRP inflammasome stimulate cytokine and chemokine production through intracellular STAT and NFκβ signaling pathways. Cytokine signaling can lead to the activation or inhibition of kinases, which can subsequently phosphorylate tau and lead to soluble oligomeric and insoluble neurofibrillary tangle (NFT) aggregation. Excitotoxicity is characterized by an increase in intracellular calcium through NMDA and AMPA receptor-mediated membrane permeability driven by excess synaptic glutamate release, and ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP3R)-mediated ER calcium efflux. Calcium excitotoxicity can lead to kinase, caspase and calpain activation, which increases p-tau. In response, the mitochondria rapidly uptake cytosolic calcium leading to mitochondrial dysfunction that is characterized by a reduction in ATP synthesis, increased production of reactive oxygen species (ROS), and the release of apoptotic factors, such as cytochrome-c. Increased ROS production and decreased antioxidant function lead to oxidative stress, which activates kinases, inhibits phosphatases and modulates Pin1 activity. CX3 CL1 signaling is downregulated, resulting in increased pro-inflammatory signaling and internalization of soluble tau through the CX3 CR1. MAPK: mitogen-activated protein kinase. GSK3β: glycogen synthase kinase 3 beta. CDK5: cyclin-dependent kinase 5. NMDA: N-methyl D-aspartate. AMPA: 2-amino-3–5-methyl-4-isoxazoleproprionic acid. STAT: signal transducer and activator of transcription. NF-κB: Nuclear factor-kappa B. IL: Interleukin. TLR: Toll-like receptor. NAA: N-acetyl aspartate. Created in BioRender