4.0 Alzheimer's Disease and Traumatic Brain Injury

Alzheimer's disease and TBI
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TBI is known to have significant correlation with
development of Alzheimer's. Image adapted from

Alzheimer’s disease (AD) is influenced by both genetics and the environment [1]. There has been a significant correlation identified between suffering a traumatic brain injury (TBI) and developing Alzheimer’s disease so TBI is an important environmental factor that can influence development of the disease[2]. TBI is very prevalent in society – each year, 1.7 million people in the United States suffer a head injury[2]. TBI has been shown to cause very similar neurological changes to those observed in Alzheimer’s patients, such as increased neurofibrillary tangles (NFT’s) and amyloid-β plaques which eventually result in neuronal death, through oxidative stress triggering apoptotic cell pathways, and impaired transport and function of mitochondria [2][3].

TBI has been shown to elevate the levels of Aβ producing proteins, thereby increasing Aβ levels. It causes functional changes at the level of the synapse which result in synaptic degeneration. TBI also elevates the levels of proteins involved in Aβ degrading mechanisms, such as neprilysin and apolipoprotein E. However, genetic polymorphisms have been identified in Aβ degrading proteins, which reduce their ability to degrade Aβ. Therefore, formation of long-lasting Aβ plaques following TBI is ultimately dependent on whether or not an individual possesses polymorphisms in Aβ degrading proteins.

Correlation Between TBI and AD

Statistics on TBI and AD

Figure 1: Increased NFT's after TBI [2]
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There were increased NFT’s in TBI sufferers than in controls.
This was especially seen in individuals under 60 years old.

Correlation Between Alzheimer's and TBI [5]
Suffering TBI can increase the risk of developing Alzheimer's Disease and dementia.

The correlation between TBI and Alzheimer’s is significant. A retrospective autopsy study done on patients over 60 showed that out of those who suffered TBI, 22.3% likely had Alzheimer’s, compared to 3-11% of the population in this age group [6]. In individuals under 60, 34% of those who suffered a TBI developed neurofibrillary tangles, as compared to only 9% in controls [2]. Amyloid-β plaques were observed at 28% in both the TBI group as well as in the control, but the density of this plaque was higher in the TBI group [2].

Experimental Models Correlating TBI with AD

Figure 3: Decreased Cognitive Performance after TBI [8]
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Transgenic mice who suffered repetitive TBI
took longer to complete the Morris Water Maze task.

Figure 2: Increased Aβ plaques after TBI [8]
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There was a clear increase in Aβ plaques
in mice subjected to repetitive TBI 1
6 weeks after injury, compared to controls at this time.

There have been several experiments done to show that inducing TBI in animal models produces AD-like symptoms. These experiments involved two groups of mice – transgenic mice which overexpress the amyloid-β precursor protein (AβPP) and therefore mimic the genetic predisposition for AD, and wild-type mice. In one case, both groups of mice were subject to a TBI, and it was found that there was a loss of neurons in both groups [7]. This is indicative of neuron loss as found in AD. Repetitive TBI was shown to lead to deficits in the Morris Water Maze task in the transgenic mice, but not in the wild-type mice [8]. It was found that in the transgenic mice, TBI increased the levels of amyloid-β plaques, as well as accelerated the formation of them [8][9]. Additionally, TBI in transgenic mice was shown to increase the levels of isoprotane, a biomarker of oxidative stress [8]. TBI was also induced in wild-type pigs, and surprisingly, an increase in amyloid-β plaques was detected [10]. As well, the drug lithium, which has been shown to have protective effects against AD, was shown to reverse the AD-like effects of TBI in mice by decreasing amyloid-β plaque formation, and improving performance on the Morris Water Maze task [11]. This finding also gives evidence of similar pathologies occurring in both TBI and AD.

See also Traumatic Brain Injury and Forgetting

Functional Changes after TBI


Caspase-3 is a protease, and it plays a major role in activating apoptotic pathways in cells [12]. Additionally, it is also known to convert the amyloid-β precursor protein (AβPP) into the amyloid-β protein [13]. This protein is known to have elevated levels in individuals suffering from AD [14]. TBI has also been shown to increase the levels of Caspase-3 in axons, in addition to increasing AβPP levels itself [13]. Mutating caspase-3 sites of cleavage in APP did not result in lower Aβ production, suggesting that caspase-3 can also increase Aβ levels independently of AβPP cleavage [12]. One way in which it does this is by changing the levels of other proteins as well, as discussed in the subsequent section on BACE1. Finally, Caspase-3 has been shown to cleave the tau protein [15]. Cleaved tau proteins are more prone to aggregation, which causes an increased formation of NFT’s [15].


Figure 5: GGA3 null mice have increased BACE1 expression [1]
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GGA3 null mice were shown to have an increase in BACE1 levels,
and a subsequent increase in Aβ production.

Figure 4: Increased BACE1 levels in mice hippocampi after TBI [16]
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There was an increase in BACE1 expression in neurons in
both the ipsilateral and contralateral CA-1 region of the hippocampus following TBI.

β-secretase, also known as BACE1, is one of the main enzymes involved in converting the amyloid-β precursor protein (AβPP) into the amyloid-β protein [16]. BACE1 levels are known to be increased in Alzheimer’s patients [1]. Induced TBI in rats was shown to also increase both mRNA and protein levels of BACE1 throughout the brain in both neurons and astrocytes, and most strongly in the hippocampus [16]. TBI was also shown to known to increase the levels of AβPP throughout the brain, as well as increase the enzymatic activity of BACE1 [16]. Therefore, this is another neurological change following TBI which closely resembles AD pathology.

The molecular mechanism behind the elevation of BACE1 levels was deciphered by Walker et al, and it involves two other proteins, GGA-3 and GGA-1 [1]. GGA-3 was previously known to be a substrate of caspase-3, involved in transporting BACE1 to lysosomes for degradation [1]. Firstly, Walker et al confirmed that GGA-3 was in fact a caspase-3 substrate by showing that TBI caused an increased level of an AβPP fragment specifically cleaved by caspase-3, and that there were subsequently decreased levels of GGA3 and increased levels of BACE1 [1]. It was then hypothesized that decreased levels of GGA3 could cause increased BACE1 levels. To verify this hypothesis, GGA3 null mice were generated [1]. These mice showed an increase in BACE1 levels compared to wild-type mice [1]. In addition to increased levels, there was also increased activity of BACE1 detected in the hippocampi of the null mice, as measured by increased levels of an AβPP fragment specifically cleaved by BACE1 [1]. TBI was then induced on both GGA3 null mice and wild-type mice. It was found that there was a larger increase in both BACE1 levels and BACE1 activity in GGA3 null mice than in wild-type mice [1].

After the induced TBI it was also found that there were decreased levels of GGA1 in both null and wild-type mice [1]. This protein was previously known to be involved in preventing BACE1 accumulation in endosomes [1]. Walker et al were able to show that GGA1 was also a substrate of caspase-3, based on the fact that cleaved GGA1 produced fragment sizes specific to caspase-3 cleavage [1]. Additionally, one of the GGA1 caspase-3 fragments identified was known to act as a dominant negative molecule by blocking transport of BACE1 away from endosomes [1]. Knockdown of GGA1 in GGA3 null mice led to an even further increase of BACE1 [1]. Over the long-term, it was also shown that GGA3 and not GGA1 was responsible for prolonged upregulation of BACE1 levels, activity, and ultimately, long-term production of Aβ [1]. Finally, GGA-3 and GGA-1 were shown to have decreased levels in human AD patients [1].

Overall, Walker et al showed that after TBI, increased levels of caspase-3 decrease the levels of the caspase-3 substrates GGA-3 and GGA-1 [1]. These two proteins are involved in BACE1 degradation, and their depletion results in increased BACE1 and subsequently increased Aβ production [1]. However, other BACE1 regulatory proteins whose levels change following TBI have been identified [1]. Future research should focus on identifying the specific mechanisms by which these regulatory proteins act, as well as the roles these mechanisms play in increasing BACE1 levels following TBI.

See also Molecular Mechanisms of AD Pathology


The other main enzyme known to convert AβPP into Aβ is γ-secretase [17]. This protein is composed of four small proteins, one of which is presenilin-1 [18]. Presenilin-1 is mutated in individuals suffering from familial AD, and this mutation is known to cause an increase in Aβ production [19]. After TBI, presenilin-1 levels have been shown to increase, thereby increasing the activity of γ-secretase [18]. The increase has been found to occur in both neurons as well as glial cells [10]. Although Presenilin-1 increases levels of Aβ, it is capable of degrading Aβ as well, through the actions of the key Aβ degrading enzyme neprilysin [18][20]. As levels of presenilin-1 increase, levels of neprilysin also increase post-TBI [20]. However, there is a specific neprilysin polymorphism of increased GT repeats in its promoter region [20]. It was found that after TBI individuals who possess more than 41 total GT repeats in the promoter region have significantly increased Aβ plaques, whereas those who do not have this polymorphism do not have increased plaques [20]. At this point, the mechanism by which the polymorphism acts is unknown, but it is thought to change neprilysin levels, therefore having a direct effect on the rate of Aβ degradation [20].

Apolipoprotein E

Apolipoproteins are proteins that play a major role in repairing cells [21]. They are known to do this by transporting lipids between cells in the CNS [22]. These proteins are known to bind to an LDL receptor related protein which interacts with AβPP [22]. Suffering a TBI has been shown to increase the levels of apolipoprotein E, and this protein assists in clearing Aβ [21][22]. However, individuals who possess a specific form of apolipoprotein E, called apolipoprotein E4, have been shown to have poorer outcomes after TBI [23].

ApoE4 has been shown to enhance production of Aβ in neurons by 60%22. The exact mechanism by which this works is also unclear at the moment, however, blocking the apolipoprotein/LDL receptor interaction has been shown to decrease Aβ production [22]. ApoE4 also clears Aβ at a slower rate than other forms of the protein, further contributing to the buildup of Aβ [17]. Additionally, ApoE4 has been shown to undergo cleavage into fragments [24]. These fragments have been shown to bind to proteins in the membrane of the mitochondria. This has two effects. The first effect is that the membrane potential of the mitochondria is altered, and the second effect is that apoptotic pathways in mitochondria are triggered [24]. Both of these effects ultimately result in neuronal cell death [24]. A proposed mechanism for this ApoE4 interaction with mitochondria is that it can escape the normal secretory pathway of the cell, undergo cleavage, and the fragments can then diffuse into the cytosol and interact with mitochondria [24].

Structural Changes

Synaptic Effects

Figure 6: Synaptic changes causing increased Aβ after TBI [3]
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Some of the changes that occur around the synapse and
within neurons following TBI

Another prominent symptom of Alzheimer’s disease that precedes neuronal cell death is synapse degeneration. It has been shown in the hippocampus, a structure associated with AD, that there is an 18% loss of synapses in individuals with mild cognitive impairment, and a 55% loss of synapses in individuals with AD [3]. Synaptic degeneration is also shown to occur after TBI. TBI decreases the levels of synaptophysin, an important protein in maintain synapses, and this directly causes synaptic loss [25]. As well, there is a decrease in the levels of PSD95 [3]. PSD95 is a scaffolding protein, and it plays a major role in synaptic plasticity and LTP formation [3]. In addition to synapse loss, lower levels of PSD95 have been implicated in the decreased cognitive function following TBI that resembles AD symptoms [3].

After TBI, there are lower levels of glutamate transporters present on astrocytes, resulting in a decreased ability for astrocytes to reabsorb glutamate [3]. This leads to increased levels of glutamate at the synapse, which causes overstimulation of NMDA receptors [3]. Overstimulation of NMDA receptors increases influx of Ca2+ resulting in stronger activation of CamKII [3]. CamKII has been shown to increase expression of APP, thereby increasing Aβ [26]. Interestingly, the location of NMDA receptors is also important in this mechanism [3]. Stimulation of extrasynaptic NMDA receptors results in increased Aβ levels, but stimulation of synaptic NMDA receptors actually reduces Aβ levels [3]. The increased levels of glutamate, however have been shown to exert their effects on extrasynaptic receptors and not synaptic receptors [3].

See also Alzheimer's Disease and LTP Impairment

Related Pages

Molecular Mechanisms of AD Pathology
Traumatic Brain Injury and Forgetting
Alzheimer's Disease and LTP Impairment
Diagnosis of Alzheimer's Disease
Preventing Alzheimer's Disease
Treatment of Alzheimer's Disease

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