Thrombin, a Key Driver of Pathological Inflammation in the Brain.
Jaclyn IannucciPaula GrammasPublished in: Cells (2023)
Neurodegenerative diseases, including Alzheimer's disease (AD), are major contributors to death and disability worldwide. A multitude of evidence suggests that neuroinflammation is critical in neurodegenerative disease processes. Exploring the key mediators of neuroinflammation in AD, a prototypical neurodegenerative disease, could help identify pathologic inflammatory mediators and mechanisms in other neurodegenerative diseases. Elevated levels of the multifunctional inflammatory protein thrombin are commonly found in conditions that increase AD risk, including diabetes, atherosclerosis, and traumatic brain injury. Thrombin, a main driver of the coagulation cascade, has been identified as important to pathological events in AD and other neurodegenerative diseases. Furthermore, recent evidence suggests that coagulation cascade-associated proteins act as drivers of inflammation in the AD brain, and studies in both human populations and animal models support the view that abnormalities in thrombin generation promote AD pathology. Thrombin drives neuroinflammation through its pro-inflammatory activation of microglia, astrocytes, and endothelial cells. Due to the wide-ranging pro-inflammatory effects of thrombin in the brain, inhibiting thrombin could be an effective strategy for interrupting the inflammatory cascade which contributes to neurodegenerative disease progression and, as such, may be a potential therapeutic target for AD and other neurodegenerative diseases.
Keyphrases
- traumatic brain injury
- endothelial cells
- oxidative stress
- cerebral ischemia
- white matter
- lps induced
- cardiovascular disease
- lipopolysaccharide induced
- resting state
- cognitive impairment
- multiple sclerosis
- type diabetes
- inflammatory response
- skeletal muscle
- cognitive decline
- squamous cell carcinoma
- drug delivery
- cancer therapy
- subarachnoid hemorrhage
- binding protein
- amino acid
- risk assessment
- genetic diversity
- pluripotent stem cells