| Department of Anatomy and Cell Biology
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Anatomy and Cell Biology
Tuesday November 20 - Robert J. Vassar, Ph.D. Associate Professor, Cell and Molecular Biology Elevated BACE1 levels may play a role in the pathogenesis of Alzheimer's disease. Alzheimer’s disease (AD) is characterized by cerebral amyloid plaques that are composed of the 40-42 amino acid beta-amyloid peptide (Ab). Mounting evidence suggests that Ab plays a critical early role in the pathogenesis of AD. The formation of Ab is initiated by the b-secretase enzyme, BACE1. This transmembrane aspartic protease is a prime therapeutic target for AD, because inhibiting BACE1 should lower Ab production and thus provide therapeutic benefit for AD. Recently, it has been shown that BACE1 levels are increased in AD brain, suggesting that the elevation of BACE1 levels may promote the pathogenesis of AD. BACE1 levels are also elevated by various physiological stresses, indicating that this enzyme is a stress response protein. In addition, it has been long known that AD brain exhibits reduced energy metabolism as shown by low glucose utilization, which manifests itself early in the disease process even before memory impairment. Putting these facts together, we reasoned that impaired energy metabolism might contribute to the increase in BACE1 levels in AD, at least at early stages of disease. Indeed, we observe that BACE1 levels are elevated in the brains of AD transgenic mouse models treated with energy production inhibitors and that this leads to greater amyloid loads. We also observe increased BACE1 levels around the cores of amyloid plaques. Together, our data suggest a positive feedback mechanism in which impaired energy metabolism initiates a rise in BACE1 level that causes greater Ab production and amyloid plaque formation. Once plaques form, BACE1 levels become elevated around plaques, thus generating more Ab to increase the amyloid burden. This seminar will describe our recent work in this area and our attempts to determine the molecular mechanism responsible for elevated BACE1 levels in AD. Rodney A. Velliquette, Tracy O’Connor and Robert Vassar (2005) Energy Inhibition Elevates ß-Secretase Levels and Activity and Is Potentially Amyloidogenic in APP Transgenic Mice: Possible Early Events in Alzheimer’s Disease Pathogenesis. J. Neuroscience 25(47):10874 –10883. Holly Oakley, Sarah L. Cole, Sreemathi Logan, Erika Maus, Pei Shao, Jeffery Craft, Angela Guillozet-Bongaarts, Masuo Ohno, John Disterhoft, Linda Van Eldik, Robert Berry and Robert Vassar (2006) Intraneuronal ß-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer’s Disease Mutations: Potential Factors in Amyloid Plaque Formation. J. Neuroscience 26:10129-10140. Jie Zhao, Yifan Fu, Marina Yasvoina, Peizhen Shao, Brian Hitt, Tracy O’Connor, Sreemathi Logan, Erika Maus,
Martin Citron, Robert Berry, Lester Binder and Robert Vassar (2007) ß-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels
Become Elevated in Neurons around Amyloid Plaques: Tuesday December 4 - Lester Binder, Ph.D. Abbott Labs/Burnham Professor of Genetic and Molecular Medicine Tau proteins in neurodegeneration: Unravelling the neurofibrillary tangle. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F and Berry RW. (2005) Tau, tangles, and Alzheimer's disease. Biochim Biophys Acta. 1739(2-3):216-23. Horowitz PM, LaPointe N, Guillozet-Bongaarts AL, Berry RW and Binder LI. (2006) N-terminal fragments of tau inhibit full-length tau polymerization in vitro. Biochemistry 45(42):12859-12866. Reynolds MR, Reyes JF, Fu Y, Bigio EH, Guillozet-Bongaarts AL, Berry RW and Binder LI. (2006) Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies. J Neuroscience 26(42):10636-10645. |
