Traumatic brain injury (TBI) is the strongest environmental risk factor for Alzheimer's disease (AD). Clinical and experimental TBI is associated with accelerated beta-amyloid (Abeta) deposition, a hallmark of AD pathology. The Abeta peptide is derived by serial proteolysis of amyloid precursor protein (APP) by beta-secretase at the N-terminus followed by gamma-secretase at the C-terminus. Beta-site APP-cleaving enzyme (BACE) has been identified as beta-secretase. BACE levels are elevated in AD brain, and BACE is induced as a stress-related protease following cerebral ischemia and TBI in rodents. We recently reported that BACE and beta-secretase activity increase following cerebral ischemia in vivo and caspase activation in vitro due to post-translational stabilization of BACE protein. We also found that the impaired degradation of BACE is due to caspase- mediated depletion of GGA3, an adaptor protein involved in BACE trafficking (Tesco et al. 2007). In the current proposal, we report that genetic ablation of GGA3 increases levels of BACE in the brain in vivo. Furthermore, we have found that GGA3 is depleted following TBI while BACE protein levels increase with a pattern similar to the one observed following cerebral ischemia. These new findings indicate that GGA3 depletion, mediated by caspase cleavage, and consequent BACE upregulation may be the common underlying mechanism of increased A? production following cerebral ischemia and TBI. Since Abeta has been shown to impair synaptic transmission, increased Abeta levels may be responsible for impaired functional outcome after TBI. This mechanism may also explain how TBI leads to increased risk of developing AD over time. In support of our hypothesis, we have found that GGA3 levels are decreased in both temporal cortex and cerebellum from AD subjects, suggesting that subjects with lower levels of GGA3 could be at greater risk of developing AD (Tesco et al. 2007). This may be particularly true for patients with stroke and TBI in which caspase activation occurs even in the chronic period after injury. The long-term goal of this proposal is to identify targets for novel treatments to prevent acute learning and memory deficits as well as development of AD following TBI. We propose the following specific aims: 1) determine the extent to which depletion of GGA3 regulates levels and activity of BACE and causes behavioral changes in mice;2) determine the extent to which decreased levels of GGA3 affect BACE levels and activity and functional outcome following TBI in mice;3) determine the extent to which lack or low levels of GGA3 exacerbate A? deposition in a mouse model of AD pathology (Tg2576 transgenic mice expressing human APP with the "Swedish" mutation (KM670/671NL)) in normal conditions and following TBI.
It has been known for several years that traumatic brain injury (TBI) can increase the risk of Alzheimer's disease (AD), but the mechanism underlying that increased risk has not been understood. Our work shows that head trauma, can trigger a series of biochemical events that increase the production of beta-amyloid, the toxic peptide that accumulates in the brain of AD patients. Thus, we propose to use mouse models to determine whether the inhibition of ?-secretase, one of the enzymes responsible for the production of amyloid-beta, ameliorates the cognitive deficits and reduces AD pathology following head trauma. Furthermore, we propose to determine whether low levels of the trafficking molecule GGA3, which regulates b-secretase, may represent a novel risk factor for the development of cognitive deficits and AD following TBI using a mouse model in which the GGA3 gene has been deleted. Overall, the outcome of this study will help to identify novel therapies to prevent both short-term cognitive deficits and the development of AD in subjects affected by TBI.
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