Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury

Abstract

Amyloid-β (Aβ) peptides, found in Alzheimer's disease brain, accumulate rapidly after traumatic brain injury (TBI) in both humans and animals. Here we show that blocking either β-or γ-secretase, enzymes required for production of Aβ from amyloid precursor protein (APP), can ameliorate motor and cognitive deficits and reduce cell loss after experimental TBI in mice. Thus, APP secretases are promising targets for treatment of TBI.TBI is the leading cause of mortality and disability among young individuals in developed countries, and globally the incidence of TBI is rising sharply 1 . TBI is a disease process, with an initial injury that induces biochemical and cellular changes that contribute to continuing neuronal damage and death over time. This continuing damage is known as secondary injury, and multiple apoptotic and inflammatory pathways are activated as part of this process (for reviews, see refs. 2,3 ). TBI is a major risk factor for the development of Alzheimer's disease 4,5 , and post-mortem studies show that 30% of TBI fatalities have Aβ deposits 6,7 . Remarkably, these deposits may occur less than 1 d after injury 8 . Not only does Aβ accumulate after TBI 9,10 , but also do the necessary APP enzymes responsible for Aβ production: β-APPcleaving enzyme-1 (BACE1) and presenilin-1, a γ-secretase complex protein [11][12][13][14] . Although the role of the APP secretases in secondary injury is unknown, multiple lines of evidence show that Aβ can cause cell death, activate inflammatory pathways [15][16][17][18] and prime proapoptotic pathways for activation by other insults 19 . The APP secretases may also be directly involved in secondary injury, as over-expressed BACE1 alone has been shown to cause neuronal cell loss in the absence of Aβ accumulation 20 . These facts make the APP secretases a potential therapeutic target for TBI.In our initial experiments, we characterized the TBI-induced protein changes in a nontransgenic mouse. We performed TBI by controlled cortical impact (CCI) of the left parietal cortex. This model induces both necrotic and apoptotic cell death, causing brain lesion and the development of behavioral deficits 21 . It has recently been reported that interstitial fluid Aβ concentrations correlate with neurological function in the injured human brain, with Aβ accumulating as neurological function improved in the days after trauma 22 . Exposure to experimental TBI resulted in accumulation of endogenous mouse Aβ x-40 peptide in the ipsilateral cortex within 1 d (Fig. 1a). Aβ levels increased by almost 120% at 3 d after injury before normalizing by 7 d (Fig. 1a) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBace1 and presenilin-1 (Fig. 1b), as has been previously reported in other animal models and humans 9-14 . Soluble APP-α, which is purported to be neuroprotective 23 , was also increased after injury. Functionally, this model of TBI causes deficits in fine motor coordination (beam walk test, Supplementary Fig. 1a online) in the absence of gross motor def...

Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

“…We have found previously that the CCI model of TBI results in reduced neuronal cells in the hippocampus, 14 and again in this study there were noticeably less Golgi-positive CA1, CA2, and dentate gyrus neurons visible in the ipsilateral hippocampus compared with the contralateral hippocampus of the same mouse (Fig. 1D).…”

“…14 Here we examined the acute effects of a second inhibitor LY450139, which we would expect to have similar protective effects after TBI as DAPT. While we do not see an effect of c-secretase inhibition on spine loss, it is difficult to extrapolate the lack of effect of our acute data to the longer-term motor and cognitive benefit we found in a 3-week treatment study.…”

“…14,22 Because Ab can cause dendritic spine loss in vitro and in vivo, 18,19 we wanted to determine the role of Ab accumulation on spine loss after TBI.…”

“…The rapid accumulation of Ab after TBI is well documented in both humans and experimental animal models. [12][13][14][15][16][17] Excess Ab is detrimental to dendritic spine health both in vivo 18 and in vitro 19 and, similar to spine loss after TBI, Ab-induced dendritic spine loss can be prevented with the calcineurin inhibitor FK506. 20 These data suggest that spine retraction after Ab and TBI may have a common mechanism of action through calcineurin activation.…”

miR-711 upregulation induces neuronal cell death after traumatic brain injury

“…Moderate-level injury was induced using an impactor velocity of 6 m/s and deformation depth of 2 mm as previously described. 46 After injury, the incision was closed, anesthesia terminated and the animal placed into a heated cage to maintain normal core temperature for 45 min post-injury. Sham-injured animals underwent anesthesia and surgical procedures but without cortical impact.…”