Abstract
Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer’s disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to Aβ and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without Aβ. S100A9 and Aβ plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.
Highlights
Over the past decade traumatic brain injury (TBI) has become the focus of increasing attention due to frequent incidences in modern society, including sport and military injuries
This is why we have examined TBI, which is considered as a precursor state or risk factor for AD12,51,61
TBI was linked to Alzheimer’s disease (AD) via the amyloid cascade and aggregation of amyloid-β peptide (Aβ) peptide
Summary
Over the past decade traumatic brain injury (TBI) has become the focus of increasing attention due to frequent incidences in modern society, including sport and military injuries. We have found that pro-inflammatory mediator S100A9 can serve as a critical link between the amyloid cascade and neuroinflammatory events in AD10. Being highly amyloidogenic itself S100A9 can trigger and aggravate Aβ amyloid self-assembly and significantly contribute to amyloid cytotoxicity[10,11]. Both Aβ pathology[12,13] and neuroinflammation[14,15] are the key culprits in TBI secondary events, indicating that once these processes are initiated in TBI they can be further exacerbated in AD. We explore how this progression may occur with the focus on pro-inflammatory S100A9 and its role in the amyloid-neuroinflammatory cascade. It has been shown that S100A9 and its fibrils regulate the NLRP3 inflammasome by acting as priming agents[30,31]
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