**4. AD pathology in animal models of brain trauma**

Several experimental animal models of TBI have been utilized in the attempt to replicate amyloid and tau pathologies, as well as other proteinopathies associated to AD. Some of these have been summarized in **Table 2**. Animal models of TBI show elevated Aβ levels, Aβ production, and Aβ deposition, specific to the brain region and anatomy and varying with the type of injury. Observed in mice

**145**

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

that overexpress normal human APP, there is an increase in tissue concentrations of Aβ after injury, associated with an increase in hippocampal neuronal death and memory impairment [43]. However, TBI alone does not seem to induce acute plaque formation systematically. Controlled cerebral impact (CCI) injury in an APP transgenic mouse model (PDAPP) has been shown to result in a spike in Aβ40 and Aβ42, peaking at 2 h post-injury and returning to baseline by 6 h [90]. Studies in PDAPP mice over greater intervals have shown that CCI can decrease the deposition of Aβ in the ipsilateral cortex and hippocampus, up to 4–8 months after injury, compared to the uninjured side of the brain [91]. Additionally, CCI injuries, using in a different APP transgenic mouse model (Tg2576), have been shown cause elevated soluble and insoluble cortical Aβ40 and Aβ42 levels as well as amyloid plaque deposition [92]. Finally, studies in APPNLh/NLh mice, a genetargeted mouse model that expresses normal levels of human APP, yielded elevated Aβ40 levels via inhibition of caspase-3 activity, only for the first 24 h after CCI, while Aβ42 levels remain elevated through 14 days [43]. Repetitive TBI is known to cause cumulative damage. After mild TBI in mice, during two consecutive days, studies have reported delayed recovery from fine motor coordination deficits as well as evidence of enhanced blood-brain barrier breakdown accompanied by axonal injury [21]. A recent study in an animal model using a triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of repetitive mild TBI caused an increase of tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to

In contrast, repetitive TBI in a Tg2576 APP-transgenic mice model did result in greater Aβ deposition as well as an increase in the production of both soluble and insoluble cortical Aβ40 and Aβ42, which may be a result of the higher levels of oxidative stress after repetitive TBI [92]. However, TBI does not lead to early amyloid plaque formation in transgenic mice, and at later times there is a reduction in amyloid plaques in ipsilateral injury regions [90, 91]. Also, Aβ accumulation was identified in damaged axons shortly after brain injury, albeit still in the absence of Aβ plaques [94, 95]. However, the lack of evidence of Aβ deposition in non-transgenic animals was attributed, in part, to differences in the Aβ peptides found in different species. Experimental results of moderate and severe TBI studies in transgenic models of AD are also contrasted with that seen in human TBI (**Table 1**). First, rapid Aβ deposition has not been demonstrated in any of the described transgenic models, unlike human studies [34, 36, 96, 97]. Second, increased severity of the injury does not result in increased Aβ deposition; instead, it seems to correlate with reduced Aβ deposition or possibly resolution of previously established plaques, as reported by [98]. In summary, all the animal models mentioned above provide important information regarding the potentially detrimental consequences of elevated Aβ levels following TBI. However, post-traumatic Aβ deposition has not been observed in the majority of non-transgenic animal studies; most failed to identify plaque pathology that is commonly observed following human TBI. To better understand the effects of repeat trauma on the brain, an animal model that can model the disease after repetitive trauma is required. Unfortunately, such an experimental model does

**5. Apolipoprotein E4 allele and TBI increase the risk of developing AD**

The epidemiology of both AD and TBI are dominated by a single genetic risk factor, the APOE genotype. In humans, there are three distinct isoforms of

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

be involved in tau phosphorylation [93].

not yet exist and will be challenging to generate.

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

that overexpress normal human APP, there is an increase in tissue concentrations of Aβ after injury, associated with an increase in hippocampal neuronal death and memory impairment [43]. However, TBI alone does not seem to induce acute plaque formation systematically. Controlled cerebral impact (CCI) injury in an APP transgenic mouse model (PDAPP) has been shown to result in a spike in Aβ40 and Aβ42, peaking at 2 h post-injury and returning to baseline by 6 h [90]. Studies in PDAPP mice over greater intervals have shown that CCI can decrease the deposition of Aβ in the ipsilateral cortex and hippocampus, up to 4–8 months after injury, compared to the uninjured side of the brain [91]. Additionally, CCI injuries, using in a different APP transgenic mouse model (Tg2576), have been shown cause elevated soluble and insoluble cortical Aβ40 and Aβ42 levels as well as amyloid plaque deposition [92]. Finally, studies in APPNLh/NLh mice, a genetargeted mouse model that expresses normal levels of human APP, yielded elevated Aβ40 levels via inhibition of caspase-3 activity, only for the first 24 h after CCI, while Aβ42 levels remain elevated through 14 days [43]. Repetitive TBI is known to cause cumulative damage. After mild TBI in mice, during two consecutive days, studies have reported delayed recovery from fine motor coordination deficits as well as evidence of enhanced blood-brain barrier breakdown accompanied by axonal injury [21]. A recent study in an animal model using a triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of repetitive mild TBI caused an increase of tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau phosphorylation [93].

In contrast, repetitive TBI in a Tg2576 APP-transgenic mice model did result in greater Aβ deposition as well as an increase in the production of both soluble and insoluble cortical Aβ40 and Aβ42, which may be a result of the higher levels of oxidative stress after repetitive TBI [92]. However, TBI does not lead to early amyloid plaque formation in transgenic mice, and at later times there is a reduction in amyloid plaques in ipsilateral injury regions [90, 91]. Also, Aβ accumulation was identified in damaged axons shortly after brain injury, albeit still in the absence of Aβ plaques [94, 95]. However, the lack of evidence of Aβ deposition in non-transgenic animals was attributed, in part, to differences in the Aβ peptides found in different species. Experimental results of moderate and severe TBI studies in transgenic models of AD are also contrasted with that seen in human TBI (**Table 1**). First, rapid Aβ deposition has not been demonstrated in any of the described transgenic models, unlike human studies [34, 36, 96, 97]. Second, increased severity of the injury does not result in increased Aβ deposition; instead, it seems to correlate with reduced Aβ deposition or possibly resolution of previously established plaques, as reported by [98]. In summary, all the animal models mentioned above provide important information regarding the potentially detrimental consequences of elevated Aβ levels following TBI. However, post-traumatic Aβ deposition has not been observed in the majority of non-transgenic animal studies; most failed to identify plaque pathology that is commonly observed following human TBI. To better understand the effects of repeat trauma on the brain, an animal model that can model the disease after repetitive trauma is required. Unfortunately, such an experimental model does not yet exist and will be challenging to generate.

#### **5. Apolipoprotein E4 allele and TBI increase the risk of developing AD**

The epidemiology of both AD and TBI are dominated by a single genetic risk factor, the APOE genotype. In humans, there are three distinct isoforms of

*Amyloid Diseases*

**3.4 TDP-43 pathology**

cleaved tau (c-tau), including the AT8 epitope [75]. Hyperphosphorylated Tau has been shown to increase between 1 and 7 days after moderate TBI in triple transgenic AD mice [76] and at 3 weeks after repetitive mild TBI in the human Tau (hTau) tauopathy mouse model [77] (**Table 2**). Experimental studies in animal models suggest that intra-axonal tau accumulation and tau phosphorylation may be in fact the consequences of repeated brain trauma or dementia pugilistica/CTE [78]. Today, CTE is used to define the neurological sequelae and neuropathological changes that occur as a result of repeat concussive or subconcussive blows to the head. Besides, the pathology of CTE is also characterized as a tauopathy, a class of neurodegenerative disease caused by the pathological aggregation of tau protein [78]. In CTE, NFTs also consist of hyperphosphorylated and ubiquitinated tau [79, 80]. Tau degradation in boxers with CTE are structurally and chemically similar to those seen in AD and frontotemporal lobar degeneration (FTLD) [80]. Treatment with γ-secretase inhibitors diminishes amyloid pathology but does not affect TBI-induced tangle formation, suggesting that TBI-induced tau pathology is not a

TAR DNA-binding protein (TDP-43) protein has been identified as a regulator of gene expression and exon splicing with DNA and RNA binding capabilities. Hence, though TDP-43 is synthesized in the cytoplasm and resides in the nucleus of neurons and glia, under pathological conditions TDP-43 is accumulated in the cytoplasm in the form of ubiquitinated and hyperphosphorylated inclusions [82] (**Figure 1**). Pathological TDP-43 has been identified as the main disease-associated protein in ALS and FTLD. It has also been recognized as a secondary feature in many other neurodegenerative diseases, including Huntington disease, AD and PD [83]. Axonal damage results in an upregulation of TDP-43 expression, together with a redistribution of TDP-43 from the nuclear compartment to the cytoplasm [33, 84]. TBI induces TDP-43 abnormalities that can contribute to the neurological consequences of TBI, such as worse cell death, and cognitive deficits [85]. TDP-43 proteinopathy is also part of the acute or delayed pathological sequelae of repetitive mild, concussive TBI or CTE pathogenesis [86, 87]. The TDP-43 proteinopathy associated with CTE is similar to that found in FTLD with TDP-43 inclusions [87]. Intraneuronal accumulation of non-phosphorylated TDP-43 after a single TBI has also been reported [88]. Contrarily, related studies failed to demonstrate an association between single TBI and TDP-43 proteinopathy, only with repetitive TBI, indicating that just many insults reinforcing acute upregulation are sufficient to cause TDP-43 aggregation. Importantly, aggregates of phospho-TDP-43 were not increased long-term following TBI [88]. To the best of our knowledge, a clear functional role of altered TDP-43 expression levels after TBI has not been demonstrated, though this might disrupt signaling pathways involved in neuronal

downstream event of Aβ and plaque formation [81].

dysfunction, as some authors have suggested [89].

**4. AD pathology in animal models of brain trauma**

Several experimental animal models of TBI have been utilized in the attempt to replicate amyloid and tau pathologies, as well as other proteinopathies associated to AD. Some of these have been summarized in **Table 2**. Animal models of TBI show elevated Aβ levels, Aβ production, and Aβ deposition, specific to the brain region and anatomy and varying with the type of injury. Observed in mice

**144**

the protein: apoE2, apoE3, and apoE4, distinguished by three alleles [99]. The apoE ε4 allele confers strong susceptibility for AD and is also the factor for the development of amyloid plaques after TBI. Furthermore, the apoE ε4 allele has been associated with increased Aβ in the cerebral cortex and unfavorable outcome after TBI [100]. ApoE4 individuals were over 10 times more likely to develop AD after severe TBI than those who did not posse the allele [101], and the presence of an apoE4 allele is linked to poor recovery from extended coma. Professional boxers containing the apoE ε4 allele were at increased risk of CTE compared to boxers without the apoE ε4 allele [102]. This finding suggests that genetic factors may strongly influence the risk of CTE after brain injury. However, the possibility remains that certain boxers may be innately 'resistant' to developing AD or dementia following CTE; definitely, not all boxers go on to develop AD, despite repetitive injury and having the higher risk genotype. Consistent with a role of ApoE protein in amyloid deposition in humans, apoE4 also increases amyloid plaque formation in mice. Aβ deposition is also significantly increased following head trauma in PDAPP (platelet-derived growth factor promoter expressing amyloid precursor protein) mice carrying the human apoE ε4 allele versus those carrying apoE ε3 or no apoE (**Table 2**) [103]. Finally, transgenic APOE ε4 mice, which also overexpress APP, show accelerated deposition of Aβ following injury, suggesting apoE ε4 may reduce the clearance of Aβ, thereby favoring its deposition [100] (**Table 2**). Some recent reports are controversial clinical and preclinical studies about the link between poor outcome after severe and mild TBI and the APOE4 gene [11, 16, 30, 104, 105].
