1. Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease
- Author
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Sangram S. Sisodia, Rudolph E. Tanzi, Chengzhi Yu, Anne M. Danks, Soan Cheng, Gonul Velicelebi, Kenneth A. Stauderman, Kwangwook Ahn, Yue-Ming Li, Elizabeth J. Ackerman, Dan Comer, Paul J. Digregorio, Phuong T. Nguyen, William T. Comer, Long Mao, David P. M. Pleynet, Xulun Zhang, Maria Z. Kounnas, Steven L. Wagner, William C. Mobley, and Curtis M. Tyree
- Subjects
Genetically modified mouse ,Male ,Neuroscience(all) ,Transgene ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Transfection ,Presenilin ,Article ,Antibodies ,Amyloid beta-Protein Precursor ,Mice ,Cricetulus ,Alzheimer Disease ,Cricetinae ,mental disorders ,medicine ,Fluorescence Resonance Energy Transfer ,Presenilin-1 ,Animals ,Humans ,Senile plaques ,Enzyme Inhibitors ,Receptor ,Cells, Cultured ,Analysis of Variance ,Amyloid beta-Peptides ,biology ,Dose-Response Relationship, Drug ,Receptors, Notch ,Chemistry ,Hydrocarbons, Halogenated ,General Neuroscience ,medicine.disease ,Cadherins ,Molecular biology ,Peptide Fragments ,Rats ,Mice, Inbred C57BL ,Butyrates ,Disease Models, Animal ,Gene Expression Regulation ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,biology.protein ,Female ,Alzheimer's disease ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,Intracellular - Abstract
Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Abeta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).
- Published
- 2010