Amyloid deposited in the brains of Alzheimer's disease (AD) patients is composed of a 4kDa amyloid beta peptide or A-beta. A-beta is produced by sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. A novel type-1 integral membrane aspartyl protease BACE has been identified as the beta-secretase, and knock-out mouse models demonstrate that this enzyme is necessary for A-beta production in the mouse brain. The generation of A-beta by beta-secretase is a minor pathway of APP processing, resulting in 10% of APP processing to its secreted derivatives. Since BACE is a poorly active enzyme in vitro, it has been proposed that its activity is limiting in the cell. However, A-beta production increases by several orders of magnitude in transfected cells expressing high levels of APP without a corresponding increase in BACE activity. To explain these discrepant observations, the PI proposes the hypothesis that APP processing by BACE occurs in a specialized cellular compartment where its activity is not limiting. Instead, only a small pool of APP enters this compartment, accounting for the limiting processing of APP by BACE. This hypothesis is consistent with recent findings from the PI's laboratory indicating that BACE can be isolated as highly active high molecular weight complex from guinea pig brain. To further test this hypothesis, in aim 1 APP chimeras will be generated to target APP to specialized cellular compartments, and its processing will be examined.
In aim 2, the effects of cholesterol, a known stimulator of beta-secretase processing, will be evaluated on the levels and activity of BACE complex.
In aim 3, the basis of enhanced BACE activity in the complex will be evaluated. ? ?
| Pappolla, Miguel; Sambamurti, Kumar; Vidal, Ruben et al. (2014) Evidence for lymphatic A? clearance in Alzheimer's transgenic mice. Neurobiol Dis 71:215-9 |
| Pinnix, Inga; Ghiso, Jorge A; Pappolla, Miguel A et al. (2013) Major carboxyl terminal fragments generated by ?-secretase processing of the Alzheimer amyloid precursor are 50 and 51 amino acids long. Am J Geriatr Psychiatry 21:474-83 |
| Maloney, Bryan; Sambamurti, Kumar; Zawia, Nasser et al. (2012) Applying epigenetics to Alzheimer's disease via the latent early-life associated regulation (LEARn) model. Curr Alzheimer Res 9:589-99 |
| Yu, Jin; Gattoni-Celli, Marco; Zhu, Hong et al. (2011) Vitamin D3-enriched diet correlates with a decrease of amyloid plaques in the brain of A?PP transgenic mice. J Alzheimers Dis 25:295-307 |
| Sambamurti, Kumar; Greig, Nigel H; Utsuki, Tadanobu et al. (2011) Targets for AD treatment: conflicting messages from ?-secretase inhibitors. J Neurochem 117:359-74 |
| Ramesh, Balenahalli N; Rao, T S Sathyanarayana; Prakasam, Annamalai et al. (2010) Neuronutrition and Alzheimer's disease. J Alzheimers Dis 19:1123-39 |
| Prakasam, Annamalai; Muthuswamy, Anusuya; Ablonczy, Zsolt et al. (2010) Differential accumulation of secreted AbetaPP metabolites in ocular fluids. J Alzheimers Dis 20:1243-53 |
| Li, Yazhou; Duffy, Kara B; Ottinger, Mary Ann et al. (2010) GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J Alzheimers Dis 19:1205-19 |
| Poeggeler, Burkhard; Sambamurti, Kumar; Siedlak, Sandra L et al. (2010) A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan. PLoS One 5:e10206 |
| Lockrow, Jason; Prakasam, Annamalai; Huang, Peng et al. (2009) Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol 216:278-89 |
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