Alzheimer?s disease (AD) is the most common neurodegenerative disease. Although the pathological features of AD have been well described, there is still no cure for this devastating disease. For the past thirty years, AD treatment strategies have largely been focused on decreasing amyloid deposition of ?-amyloid peptides (A?), which are generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and ?-secretase. Mice deficient in BACE1 show almost abolished production of A?, confirming that BACE1 is a viable therapeutic target for testing the ?amyloid cascade? hypothesis. Most recently, chemical inhibition of BACE1 has been shown to significantly reduce A? generation, providing great promise for AD therapy. However, complete genetic deletion of BACE1 in mice actually increases the incidence of epileptic seizures (Hu et al., 2010; Hitt et al., 2010), suggesting a potential mechanism-based side effect associated with BACE1 inhibition. Our lab has recently generated BACE1 conditional knockout mice (BACE1fl/fl) by utilizing a targeting vector containing two loxP sites flanking exon 2 of BACE1. BACE1fl/fl mice were crossed with Tg-Nes-cre mice, which express Cre-recombinase in nervous tissue by embryonic day 11 under the control of nestin promoter (Graus-Porta et al., 2001), to obtain Nes-cre;BACE1fl/fl mice. Like BACE1-null mice, we found that Nes-cre;BACE1fl/fl mice also develop epileptic seizures beginning during early development. Considering the fact that epileptiform activity and seizures occur more frequently in AD patients (Hesdorffer et al., 1996; Amatniek et al., 2006; Larner, 2009), and particularly in younger AD patients (Scarmeas et al., 2009), we will investigate whether BACE1 inhibition impacts seizure activity in AD patients. We propose to test the central hypothesis that deleting BACE1 in the adult will reduce epileptic seizures by decreasing A? production in AD mouse models. To test this hypothesis, we will utilize newly generated conditional mouse models to address the following two specific aims:
Aim 1 : To investigate whether deletion of BACE1 in adult BACE1fl/fl mice induces abnormal seizure activity and whether seizure activity is altered when BACE1 is inhibited in the adult AD mouse model.
Aim 2 : To explore mechanism underlying epileptic seizures upon deletion of BACE1. Through this study, we will answer whether decreasing A? production in the adult could reduce potentially unwanted side effects such as epileptic seizures, or whether BACE1 inhibitors should be used with caution because they could increase the propensity of epileptiform activity.
Providing safe treatment for Alzheimer?s disease (AD) patients by using ?-secretase inhibitors requires multiple experimental approaches. This study is designed to investigate whether significant and sustained inhibition of ?-secretase, also known as ?-site amyloid precursor protein cleaving enzyme 1 (BACE1), will cause unwanted side effect associated with abnormal seizures. AD patients do have a higher tendency to develop seizures, and BACE1 deficiency also causes seizures. However, it is not known whether genetic deletion or chemical inhibition of BACE1 in adult mice, especially in AD mouse models, will cause seizures. This study aims to answer this specific question in order to provide therapeutic guidance for BACE1 inhibition in humans.
