Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

Abstract

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

Figure 1

Neuropathological and biochemical changes post-TBI. TBI neuropathological sequelae are linked to several pathological processes including (A) NLRP3 inflammasome activation, neuroinflammation and microglial activation, tau hyperphosphorylation, oxidative stress as well as an axonal shearing as in diffused brain injury. This is coupled with (B) elevated mitochondrial dysfunction and ROS secretion. Created with BioRender.com. DAMPs: Damage association molecular patterns; NLRP: nucleotide-binding oligomerization domain-like receptor protein 3; ROS: reactive oxygen species; TBI: traumatic brain injury.

Figure 2

Schematic of 2N4R Tau Protein Structure and the proposed epitope sites for anti-tau binding. (A) Tau protein contains major structural domains including N-terminal domain with N1 and N2 inserts, proline-rich region, four major microtubule-binding repeats (R1–R4), anti-tau antibodies act at the step of oligomer formation from these aggregates, which are precursors to neurofibrillary tangles. (B) Monoclonal antibodies (listed) equipped with recognition sequences bind to indicated regions along the 441kd human tau protein, some at specified serine, threonine, and/or tyrosine residues, or along a range of residues along the total tau protein (epitopes corresponding to each antibody is listed in Additional Table 2). Created with BioRender.com. AD: Alzheimer’s disease; CTE: chronic traumatic encephalopathy; NFTs: neurofibrillary tangles.

Figure 3

Brain atrophy tau/p-tau distribution in CTE and AD. Brain atrophy occurs in both CTE and AD and includes shrinking of functional parenchyma, depositions of misfolded tau protein, and ventricular enlargement. CTE is pathognomonic for p-tau distribution along the periphery of cerebral vessels and within the depths of cortical sulci. Atrophy typically begins with corpus callosum and other white matter structures and can progress to frontal and medial temporal lobe atrophy. AD is characterized by neurotoxic p-tau distributions in the frontal cortex and the CA1 region of the hippocampus. Tau pre-tangles and NFTs are observed in the cortical layers with resultant atrophy of temporal lobe structures. Created with BioRender.com. AD: Alzheimer’s disease; CTE: chronic traumatic encephalopathy; NFTs: neurofibrillary tangles; p-tau: phosphorylated tau; TBI: traumatic brain injury.

Figure 4

Hyperphosphorylation of endogenous tau protein leads to microtubule instability and protein misfolding that results in the formation of neurotoxic tau aggregates, prolonging pathological neuroinflammation. Tau is an endogenous microtubule-associated protein that functions to maintain cytoskeletal stability and structure. When kinase-mediated hyperphosphorylation occurs, tau protein detaches from microtubules and impairs cytoskeletal stability. Resulting in tau monomers losing their physiologically relaxed conformation and misfolding into pathological β-pleated sheets due to electrical charges generated by phosphorylation. Protein misfolding causes tau monomers to aggregate into tau oligomers, which can further aggregate into neurofibrillary tangles, ultimately leading to pyroptosis or cellular death by pore formation. Additionally, new research shows evidence for the parallel ability of tau oligomers to generate prion-like tau seeds, which propagate pathologically, causing the spread of neurotoxic tau to adjacent and even contralateral brain regions. Tau oligomers have been shown to activate pro-inflammatory mediators including interleukin-1β (IL-1β), that may further lead to physiological tau hyperphosphorylation and result in neurodegeneration. This figure depicts a cyclical pathway by which aberrant neuroinflammation is prolonged as is seen in traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease. Created with BioRender.com.

Figure 5

NLRP3 inflammasome activation and assembly pathway. Traumatic brain injury-induced brain damage and other neuroinflammatory triggers involve the release of damage-associated molecular patterns (DAMPs) that act as priming signals and trigger transcriptional upregulation of NLRP3 and pro-IL-1β through the TLR/NF-κβ pathway. Following priming, several activating signals induce the oligomerization of the inflammasome sensors (NLRP3), followed by the recruitment of ASC and pro-caspase-1, resulting in a complete NLRP3 inflammasome complex. The second step in deploying the inflammasome complex is activation, which can occur by several biochemical mechanisms including K⁺ efflux, Ca²⁺ influx, mitochondrial injury-induced ROS release, and lysosomal destabilization. Downstream caspase-1 subsequently cleaves pro-GSDMD into active GSDMD, allowing for pore formation and pyroptosis. Cell death results in the leakage of intracellular contents into the extracellular space. This process triggers the release of pro-inflammatory cytokines that further aggravate the extracellular environment and induce kinase-mediated hyperphosphorylation of tau protein. Created with BioRender.com. ASC: Adaptor molecule apoptosis-associated speck-like protein; GSDMD: gasdermin-D; IL-18: interleukin-18; IL-1β: interleukin-1β; NF-κβ: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin-domain 3; ROS: reactive oxygen species; TLR: Toll-like receptor.