The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

Abstract

The post-injury inflammatory response is a key mediator in long-term recovery from traumatic brain injury (TBI). Moreover, the immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges. For example, recent evidence shows that the presence of beta-amyloid and phosphorylated tau protein, two hallmark features of AD that increase during normal aging, substantially alter the macrophage response to TBI. Additional data demonstrate that post-injury microglia are “primed” and become hyper-reactive following a subsequent acute immune challenge thereby worsening recovery. These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology. Therefore, the purpose of this review is to summarize experimental studies examining the relationship between TBI and development of AD-like pathology with an emphasis on the acute and chronic microglial and macrophage response following injury. Furthermore, studies will be highlighted that examine the degree to which beta-amyloid and tau accumulation as well as pre- and post-injury immune stressors influence outcome after TBI. Collectively, the studies described in this review suggest that the brain’s immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery will be altered.

Alzheimer's disease in the gut—Major changes in the gut of 5xFAD model mice with ApoA1 as potential key player

“…93 Like this late phase of AD, the secondary phase of traumatic CNS injury also is characterized by neuronal loss and inflammation and has even been associated with AD. [94][95][96][97][98] Sengupta et al 99 were able to show an increase of ApoA1 in serum of patients in the secondary phase of traumatic spinal cord injury. Moreover, a similar effect has been observed in scratch-wounded neuroblastoma cells: while ApoA1 decreased immediately after the injury, later-on it increased, which was interpreted as a self-protecting mechanism of the injured system.…”

Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer’s Disease

“…Since mFPI results in widespread axonal injury throughout the brain, while CCI results in a local ipsilateral cortical contusion [22], there is much evidence that white matter injury is linked to much later cognitive impairment in patients (exhaustively reviewed by Filley and Kelly) [46]. One of the proposed mechanisms is widespread and chronic neuroinflammation [47] and another is an accelerated aging of the brain [48]. It is important to remember that wild type mice recover surprisingly well following TBI.…”

Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks

“…While these mechanisms of secondary injury are often described and targeted separately in preclinical and clinical studies, it can be argued that many, if not all, work in conjunction with immune cells in the brain and periphery to induce and propagate the inflammatory response after all severities of TBI. This is important, as chronic inflammation following a brain injury is thought to be biologically linked to increased risk of neurodegeneration later in life [19]. Figure 1 describes some of the key mechanisms related to inflammation after TBI.…”