TBI is a global issue that severely affects public health and social economy [14, 15]. It is estimated that about 52,000 people die from TBI in the United States each year, and about 530,000 people are disabled by it . The brain damage caused by TBI is time-dependent, and its pathophysiological process can be divided into three major stages, which sometimes overlap with each other [17, 18]. The early stage of TBI usually occurs within 24 hours after injury, and mainly includes a series of energy metabolism disorders such as ischemic cascade caused by decreased cerebral blood flow, calcium overload, and mitochondrial dysfunction . The intermediate stage of TBI occurs within a few days after brain trauma . The occurrence and development of neuroinflammation further lead to vascular damage and destruction of the blood-brain barrier, causing the formation of cerebral edema. The final stage of TBI occurs within a few weeks or even months after the trauma, and this stage is related to the adverse neurological outcome of TBI patients . The deterioration of nerve function leads to convulsions and seizures. Neuroinflammation is an important part of TBI secondary injury, including the release of endogenous harmful substances and the activation of the innate immune system, which plays a key role in the recovery of TBI . However, the disorders of immune response regulation can also lead to secondary damage to the central nervous system. Many cytokines are released from neutrophils, microglia, immune cells and glial cells in the injured area, including anti-inflammatory factors such as IL-10, TGF-β, neurotrophic factors, IL-4, IL-13, prostaglandins and pro-inflammatory substances such as IL-10, CXCL1, IL-1, IL-6, TNF-α, etc .
In this study, we mainly studied the role of AQP4 in the progression of TBI. We showed that AQP4 knockout mice ended up with better neurological consequences after suffering from TBI. We found that the absence of AQP4 could improve the symptoms of TBI mice, protect the integrity of the BBB, promote the clearance of brain amyloid beta, and inhibit the inflammatory response in the mouse brain tissue.
Brain tissue produces a large number of potentially neurotoxic proteins, cell fragments and other metabolites in the process of metabolism. In order to maintain a steady state, these metabolic wastes need to be cleared from the brain in time. It is estimated that the adult brain needs to remove about 7 g of junk protein every day. In 2012, Iliff and Nedergaard et al. reported that a rapid cerebrospinal fluid-brain tissue fluid exchange flow system is widely distributed in the brain, which can promote the clearance of soluble proteins such as β-amyloid protein in the brain . The flow system has the function of flushing and cleaning brain tissue, and is one of the ways for the brain to remove metabolites and foreign bodies. This system is called the glymphatic system, because it is similar in function to the peripheral lymphatic system and relies on astrocytes . Recent studies have shown that in addition to removing brain metabolites (such as lactic acid), soluble proteins (such as Aβ and Tau protein) and foreign bodies, the glymphatic system also has the ability to transport glucose, lipids and apolipoprotein E(ApoE) and other nutrients and neuroactive substances to the brain tissue . Therefore, the glial lymphatic system is an important fluid flow system that maintains the homeostasis of the cerebral environment. Iliff et al. reported that TBI can significantly inhibit the influx of the mouse cerebrospinal fluid tracer (OA-45), reducing the function of the glial lymphatic system by about 60% . They also found that cerebrospinal fluid influx and Aβ clearance can be impaired markedly in the ipsilateral hippocampus 1 day after TBI, and the glial lymphatic system function inhibition caused by TBI is still significant after 28 days .
In this research, we also reported the impact of the absence of the glymphatic system on the TBI process. The glymphatic system in the brain of AQP4 knockout mice is inactivated. However, the dysfunction of the glymphatic system protected the brain tissue of TBI mice. The absence of AQP4 and the obstruction of glymphatic circulation alleviated the symptoms of cerebral edema in TBI mice, improved their long-term neurological outcomes, and reduced the inflammatory response of the cerebral cortex induced by TBI.
3-Amyloid precursor protein (3-APP) is widely distributed in the central nervous system as a transmembrane protein. It has neurotrophic and neuroprotective effects, and can promote neurite growth and synapse formation. β-amyloid is the digestion product of its precursor APP under pathological conditions, and the main component of senile plaques, which is the main pathological change of Alzheimer's disease . Primary injury of TBI can induce changes in biochemical and cell biology functions, leading to continuous damage and death of neurons . This continuous damage acts as a secondary injury and causes the activation of multiple apoptosis and inflammatory pathways. After TBI, β-amyloid and APP quickly accumulate in the cerebral cortex, and the expression of APP-related secretases such as BAC-1, PS-1 and other proteins also increase accordingly . A large number of previous studies have shown that TBI is an independent risk factor for AD . AD plaques are formed within a few hours after TB1, and it has nothing to do with age. This may be related to AD-like pathological changes and AD-like cognitive impairment. In this study, we also explored the effect of the absence of AQP4 on the clearance of β-amyloid in the mouse brain. We reported that AQP4 knockout improved the clearance of β-amyloid in the cerebral cortex after TBI. AQP4-deficient mice lack the glymphatic system, which allows them to clear β-amyloid in other ways that are not easily affected by TBI.