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Traumatic brain injury is now well known as a condition wherein a single injury induces biochemical and cellular changes, which then contributes to continuing neuronal damage or death. Alzheimer's disease (AD) is a degenerative disease that slowly and progressively destroys brain cells. TBI induces alterations in several signaling pathways which leads to dysfunctions in synaptic plasticity, stress in endoplasmic reticulum and mitochondria and cell death. In this review, we summarize these pathways in order to emphasize the importance of TBI in relation to early development of AD. In addition, we discuss further avenues for research including future research directions.
Traumatic Brain Injury (TBI) is now well known as the leading cause of death for people under the age of 45 years (Finfer and Cohen, 2001). The annual incidence of TBI is understood to be anywhere between 100-600 people per 100,000 (Park et al., 2008). A small percentage survives after TBI but is left with severe neurological deficits which severely affect their quality of life.
Alzheimer's disease (AD) is the most common neurodegenerative disease of the modern era that contributes for 50-60% of all age-related dementia (Andersen et al., 2006). AD afflicts 8-10% of the population over the age of 65 and almost 50% of those over the age of 85(Mattson, 1997). Over 24 million people world-wide are estimated to be currently suffering from AD, and as the elderly population increases over the coming decades, the number of those suffering from AD has been estimated to rise to 81 million by 2040 (Miller et al., 2006). Research in the past decade found a strong co-relation between TBI and AD for the possibility that TBI may predispose a person to develop AD in later periods of life. This phenomenon has significant social and medical implications, and reinforces the need for preventative efforts and health service planning to cope with the potential large increase in the number of AD patients (Lye and Shores, 2000).
The first clue indicating a pathological link between TBI and AD came from the observation that Amyloid beta (Aβ) plaques, a definite sign of AD, are found up to 30% of patients who die acutely following TBI. The plaques found in TBI patients are notably similar to those observed in the early stages of AD. However, plaques in AD develop slowly and are mainly found in the elderly, whereas plaques associated with TBI can appear rapidly (within just a few hours) after injury. Although the plaques observed following trauma are typically diffuse, like those observed in early AD, it is not known whether these plaques mature over time into the denser, neuritic plaques typical of advanced AD (Van Den Heuvel et al., 2007). Although the microscopic observation of Aβ observed in patients afflicted with TBI provide a strong correlation with that of AD, but however, a concise mechanism on how Aβ formation takes place in TBI patients is still poorly understood. In view of this, this review focuses on the many signaling mechanisms that are common to both TBI and AD and in doing so, we attempt to discuss further avenues and future directions for research.
Synapse loss also exceeds the amount that would be predicted by the loss of connections from neurons that die in the brain (Coleman and Yao, 2003). This indicates that synaptic degeneration plays a central role in causing dementia. Loss of synapses is common to all neurodegenerative diseases. As such, the cause of synapse dysfunction has been the focus of many studies over the past several years for both TBI and AD. Studies by (Gao et al., 2011) showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced, and further, the function of matured granular neurons in the hippocampal dentate gyrus is impaired due to TBI insult. These observations by Gao et al (2011) could explain the potential anatomic substrate co-relating, in part, the potential development of post-traumatic memory deficits. Several potential molecular mechanisms have been suggested to underlie the detrimental synaptic effects of oligomeric Aβ. First, glutamatergic neurotransmitter receptors are known to be affected by oligomeric Aβ. NMDA receptors are required for the observed ologomeric Aβ-induced reductions in LTP (Roselli et al., 2005; Shankar et al., 2007), and oligomeric Aβ is also known to enhance LTD by causing internalization of AMPA receptors and NMDA receptors (Hsieh et al., 2006; Snyder et al., 2005). These effects on synaptic glutamate receptors are thought to be mediated at least in part by an increase in intracellular calcium which then activates calcineurin (Kuchibhotla et al., 2008; Wu et al., 2010). Non-apoptotic caspase activation is also induced by oligomeric Aβ, which could contribute to enhanced LTD and synapse loss (D'Amelio et al., 2011).
Synaptic function greatly depends on Brain-derived neurotrophic factor (BDNF) (Murer et al., 2001). In the AD brain, decreased BDNF protein levels were reported in hippocampus, entorhinal cortex, and temporal neocortex (Hock et al., 2000). A large body of research indicates that dysregulation of BDNF is found in conditions of TBI and post-traumatic stress disorder (PTSD). In TBI, BDNF reduce secondary injury, provide neuroprotection, and restore connectivity. In contrast, chronic stress or prolonged exposure to glucocorticoids can reduce BDNF levels and impair hippocampal functioning, by producing dendritic retraction, restructuring, and disconnection (Numakawa et al., 2009).
Cell survival/death signaling Mechanisms
Apoptotic and necrotic neurons have been identified with contusions in the acute post-TBI period, and these contusions are evident in regions far distant from the TBI site in days and weeks after TBI, while at the same time, there was the presence of degenerating astrocytes and oligodendtrocyes in the region within the white matter tracts. It is now generally accepted that mechanism of protein expression underlying the phenomenon of cell death is a balance between pro and anti-protein factors. Here, the effects of TBI and AD on cellular expression of various survival or death promoting proteins are reviewed.
(a) Bcl-2 family of proteins
Neurotoxin- or ischemia-mediated apoptotic death was preceded by increased Bax mRNA and protein; and decreased expression of Bcl-2 in cells was correlated to cell death (Gillardon et al., 1996; Gillardon et al., 1995) while Bcl-2 immunoreactivity was increased in neurons, glia and endothelial cells that essentially survived focal ischemic injury (Chen et al., 1995; Tortosa et al., 1998) found that Bcl-2 protein is overexpressed in reactive glial cells surrounding senile plaques, which suggests that that Bcl-2 may play a role in the survival of reactive glia in AD. Similarly, increased expression of Bcl-2 has been observed in neurons that survive the traumatic insult both in the rat and in brian-injured humans (Clark et al., 1997; Clark et al., 1999) while Bax was observed to translocate to the mitochondria of apoptotic cells following experimental brain injury (Kaya et al., 1999). In contrast, recent studies have suggested that decreases in intracellular Bcl-2 immunoreactivity, with little to no change in Bax proteins, in injured brain regions may precede cell death following experimental brain trauma (Raghupathi et al., 2003). Following experimental TBI, transgenic mice overexpressing the human Bcl-2 protein exhibited significantly less neuronal loss in the injured cortex and hippocampus, lending support to the idea that Bcl-2 may participate in the neuronal cell death following TBI (Nakamura et al., 1999; Raghupathi et al., 1998). A pro-apoptotic member of Bcl-2 family, Bid, has also been implicated in trauma-induced cell death in vivo-proteolysis of Bid preceding its translocation to the mitochondria has been demonstrated in the injured cortex (Franz et al., 2002).
(b) MAP kinases
Both JNK and ERK1/2 are known regulators of cell survival/death in a number of neural and non-neural systems in-vitro. Traumatic brain injuries appear to activate ERK1/2 in injured brain regions and appears to co-localize with both neuronal (Dash et al., 2002; Mori et al., 2002) and astrocyte (Otani et al., 2002) markers in the injured cortex and hippocampus. During progression of AD, MAPK is highly phosphorylated by GSK-3 alpha and CDK5 kinase. Whether ERK activation in injured neurons is associated with cell death or is an attempt by injured cells to maintain normal function is yet to be determined. Pre-injury treatment of animals with a specific inhibitor of ERK phorphorylation, PD98059, has been observed to decrease ERK activation and the extent of cell death after injury (Mori et al., 2002), but appears to exacerbate cognitive and motor deficits in brain injured animals (Dash et al., 2002).
(c) Tumor suppresser gene (p53) Signaling
Induction of tumor suppresser gene, (p53) mRNA has been related to neuronal damage following excitotoxic and ischemic brain injuries (Sakhi et al., 1994). Following experimental brain injury, increased mRNA and protein for p53 were observed in regions that exhibit neuronal apoptosis and in neurons that were TUNEL +ve (Hooper et al., 2007; Napieralski et al., 1999) show that upregulation of p53 induces tau phosphorylation which is a hallmark of AD. This study showed that Tau was found in the cytoskeletal compartment, while p53 was located in the nucleus, thereby indicating the fact that the effects of p53 on tau phosphorylation are indirect. Since wild type p53 is a transcription factor for genes such as wild type p53 activated fragment (WAF1/p21) (Artuso et al., 1995), the pro-apoptotic factor, Bax (Miyashita et al., 1994) and the growth arrest and DNA damage-inducible gene GADD45(Zhan et al., 1998), the consequences of p53 induction are many. Other evidences establish that p53, are also up regulated and may participate in molecular response to TBI.
(d) Akt/GSK-3 beta/beta-catenin signaling
Akt/GSK-3 beta/beta-catenin signaling plays a crucial role in the apoptosis of neurons in several of the models of neurodegeneration. Zhao et al (2012) studied the mechanism of cell survival mediated by the Akt/GSK/beta-catenin pathway using a rat model of TBI, where phospho-Akt was significantly increased at 4 hours post-TBI, but decreased after 72 hours post-TBI. Further, neuroprotection of beta-catenin against ischemia was partly mediated by increased and persistent activation of the Akt/GSK3beta signaling pathway (Zhao et al., 2012). Studies by (Lucas et al., 2001) using conditional transgenic mice overexpressing GSK-3b in vivo resulted in neurodegeneration and this suggest a direct relevance of GSK-3b deregulation to the pathogenesis of AD and TBI.
Role of Endoplasmic Reticulum (ER) dysfunction
APP is considered a transmembrane protein which appears folded and thereafter it is modified in endoplasmic reticulum (ER) and then transported through the Golgi complex to the outer membrane (Salminen et al., 2009). APP is mostly expressed in neurons but however, it is found that astrocytes and oligodendrocytes are also capable expression as well as processing of APP protein (Salminen et al., 2009). It appears that the processing can vary widely depending on the varying compartments during the process of transport from ER to lysosomes, and this depends on the cellular circumstances as well (e.g., metabolism and stress conditions) (Salminen et al., 2009).
ER is a sensitive organelle which is capable of perceiving disturbances in the cellular homeostasis and therefore it is logical to conceive the fact that the brains of AD sufferers could display many indications of ER stress (Hoozemans et al., 2009). ER is capable of defending the host by use of activating UPR (unfolded protein response). This includes cascades that are capable of withstanding the adaptive changes in metabolism and gene expression that are required to manage stressful situations. Thereafter, ER can initiate the program whereby the cells are killed but tissues are saved from necrotic injury.
Bax-Inhibitor-1 (BI-1), a cytoprotective protein which resides in ER membranes is often manifested within the context of ER stress. BI-1 modulates several ER-associated functions, including UPR signaling. Furthermore, brain tissue from BI-1 transgenic mice subjected to TBI after ER stress indicated reduced levels in apoptotic cells, inductions markers as well as CHOP protein expression.
Presenilin 1 (PS1), a polytopic membrane protein plays a central role in trafficking as well as in the proteolysis of certain set of transmembrane proteins. It is found that significant majority of individuals that are affected with the onset of familial Alzheimer's disease (FAD) often carry missense mutations of PS1. Further to this, CHOP messenger RNA is compromised in cells that lack PS1 and PS2 or, in cells that express FAD-linked PS1 variants (Sato et al., 2000).
The role of Mitochondrial dysfunction
The role of mitochondrial dysfunction and oxidative damage was investigated by several researchers. Mitochondrial dysfunction is characterized in the 3xTg-AD brain by way of reduced mitochondrial respiration and pyruvate dehydrogenase protein levels as well as activity in mice of 3 months of age. Further it expressed increased oxidative stress characterized by increased levels of hydrogen peroxide and lipid production levels. In addition to this, mitochondrial Aβ levels in 3xTg-AD female mice of 9 months age was found to be substantially increased (Reddy, 2011).
Drago et al. (2008) investigated whether Aβ-metal complexes have detrimental effects on intraneuronal Ca2+ homeostasis and mitochondrial function in vitro. Results show that Aβ perturbed neuronal Ca2+i homeostasis and in addition inhibited mitochondrial respiration. Resende et al (2008) investigated whether oxidative damage occurs early in AD development. It evaluated oxidative stress and the levels of antioxidants in the 3xTg-AD mouse model. Results show increased activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase. These increases were evident during the Aβ oligomerization period, before the appearance of Aβ plaques and NFTs, and thereby supporting the view that oxidative stress occurs early in AD development, before Aβ plaques and NFTs are observed (Resende et al., 2008).
Mitochondria also appear to play a vital role in the secondary injury that occurs after traumatic brain injury (TBI) (Finkel, 2001; Hunot and Flavell, 2001), and mitochondrial dysfunction has been shown to be involved in excitatory amino acid (EAA)-induced neurotoxicity (Brustovetsky et al., 2002). Mitochondrial dysfunction after TBI has been linked to impairment of brain mitochondrial electron transfer and energy transduction due to overloading of mitochondrion-associated calcium (Xiong et al., 1997), increased mitochondrial reactive oxygen species (ROS) production, oxidative damage, disruption of synaptic homeostasis(Azbill et al., 1997; Matsushita and Xiong, 1997; Sullivan et al., 1999), and cell death (Robertson, 2004). Following TBI, the levels of NADPH oxidase activity and superoxide production show significant elevations. This could significantly contribute to the pathophysiology of TBI via mediation of microglial activation, oxidative stress damage, and induction of amyloid beta in the brain.
TBI is one of the leading disorders that often either leads to immediate death or inflicted with a lifetime of severe cognitive disabilities. A thorough and precise understanding of the exact cause of developing AD when inflicted with TBI could potentially be beneficial for further development of therapeutics aimed to stop the onslaught of such neurodegenerative diseases.
Despite the progress in research including several clinical trials over the past decades, there isn't a single effective drug that could attenuate the cognitive dysfunction associated with TBI. Considering this, one could argue that a combination therapy i.e., targeting multiple and complimentary mechanisms of action (Margulies et al., 2009) could be an option especially for the fact that TBI affects a wide range of brain functions including physical, cognitive and behavioral. Failing clinical trials for therapeutics in TBI research has been a major concern in the past. In this regard, a uniform standard of care for clinical trials should be adopted that could necessarily mimic the standards used pre-clinical research. Finally, adoption of a shared database for interpreting positive and negative of pre-clinical data would be of great help.
Figure 1. Schematic representation of the relation between an incidence of TBI and the subsequent development of Alzheimer's disease. An incidence of TBI (indicated in red) triggers cell death, synaptic dysfunction, Endoplasmic Reticulum (ER) and mitochondrial stress leading to potential development of Alzheimer's disease (indicated in shades of blue, violent and green).