**3.1 Amyloid precursor protein (APP)**

APP and its proteolytic derivatives are important mediators of neuronal synaptogenesis and synapse maintenance [47]. APP functions in the axonal transport of vesicles and presenilin (PS) regulate intracellular protein trafficking, highlighting the role of APP as a synaptic vesicle protein [47]. TBI leads to overexpression

#### **Figure 1.**

*Relationship between neuropathological proteins induced after brain injury and the onset of Alzheimer's disease. Schematic diagram showing that traumatic brain injury (TBI) and Alzheimer's disease (AD) share similar pathological pathways (such Aβ pathologies and TDP-43 proteinopathy) and neuroinflammatory responses that potentially could explain the vulnerability of TBI patients to the onset of dementia/AD.*

**141**

peptides.

*3.2.1 Protein amyloid-β*

largely unknown.

*Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer's Disease*

of APP within neuronal cell bodies and APP accumulation within injured axons [48] (**Figure 2C**). Postmortem studies on human brain tissue samples from patients who have sustained mild TBI, but died due to other causes, have shown that APP accumulation occurs very rapidly (within a few hours) after brain [49]. Once mature, APP can be processed by two mutually exclusive complex pathways, either the non-amyloidogenic or the amyloidogenic pathway [50]. The nonamyloidogenic pathway accounts for the majority of APP processing and results in the secreted APP (sAPPα) via α-secretase cleavage [51]. The β- and γ-secretase pathway is responsible for producing secreted APPβ (sAPPβ) and the toxic Aβ, which is found within amyloid plaques in AD [52]. Both axonal APP accumulation and long-term accumulation of Aβ has been reported in injured axons following TBI [53]. This large reservoir of APP in axons might be aberrantly cleaved to form Aβ [49]. Evidence for the role of caspase-3 in APP cleavage and Aβ production has come from recent studies examining the effects of caspase inhibition following trauma [43]. APP undergoes sequential proteolysis to produce plaque-forming Aβ

Amyloid is a highly-ordered filamentous protein aggregate generally regarded as a misfolding event in which proteins that are soluble accumulate into fibrous structures [54]. However, determinants of amyloid formation and toxicity are

Edema, inflammatory response, vasculature changes, and deposition of Aβ have all been found to be localized pathological changes after TBI [55]. As such, an understanding of the mechanism promoting AD risk is important. Although TBI is typically believed to be a static pathological insult from a single event, new clinical unrecognized clinical symptoms can arise many years after the initial injury. In human studies, TBI

Aβ immunoreactivity and protein expression increase for as long as a year after injury, indicating that Aβ aggregation and plaques formation may continue long after APP gene expression returns to normal. Plaques found in TBI patients are strikingly similar to those observed in the early stages of AD [13, 14]. However, TBIassociated plaques can appear rapidly (within hours) after injury, whereas plaques

Monomeric forms of Aβ can aggregate to form oligomers, protofibrils; these fibrils deposit as amyloid plaque (**Figure 1**), unaggregated oligomeric forms of Aβ may contribute to toxicity after TBI [56]. Aβ causes apoptotic cell death of neuronal cells in culture by the induction of caspases, known instigators of apoptotic cell death [57]. Accumulation of Aβ deposits, hippocampal damage, and chronic inflammation were found mainly in subcortical regions [18]. Early microglial accumulation in AD delays disease progression by promoting clearance of neurotoxic Aβ peptides before the formation of senile plaques. However, as AD mice age, microglia become dysfunctional, producing proinflammatory cytokines in response to Aβ

The intracellular accumulation of Aβ, extracellular deposition of soluble Aβ plaques, and aggregation of tau protein have all been observed in patients, sometimes within hours after severe brain injury [59, 60]. Aβ accumulation and amyloid

has been shown to result in amyloid deposits reminiscent of AD pathology.

in AD develop slowly and are found predominantly in the elderly [13].

aggregation downregulate genes involved in Aβ clearance [58].

*3.2.2 Mechanisms of post-traumatic amyloid-β formation*

*DOI: http://dx.doi.org/10.5772/intechopen.81945*

**3.2 Amyloid β formation and amyloid plaques**

*Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.81945*

of APP within neuronal cell bodies and APP accumulation within injured axons [48] (**Figure 2C**). Postmortem studies on human brain tissue samples from patients who have sustained mild TBI, but died due to other causes, have shown that APP accumulation occurs very rapidly (within a few hours) after brain [49]. Once mature, APP can be processed by two mutually exclusive complex pathways, either the non-amyloidogenic or the amyloidogenic pathway [50]. The nonamyloidogenic pathway accounts for the majority of APP processing and results in the secreted APP (sAPPα) via α-secretase cleavage [51]. The β- and γ-secretase pathway is responsible for producing secreted APPβ (sAPPβ) and the toxic Aβ, which is found within amyloid plaques in AD [52]. Both axonal APP accumulation and long-term accumulation of Aβ has been reported in injured axons following TBI [53]. This large reservoir of APP in axons might be aberrantly cleaved to form Aβ [49]. Evidence for the role of caspase-3 in APP cleavage and Aβ production has come from recent studies examining the effects of caspase inhibition following trauma [43]. APP undergoes sequential proteolysis to produce plaque-forming Aβ peptides.
