Modulation of γ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimer's disease Journal Article
| Authors: | Kounnas, M. Z.; Danks, A. M.; Cheng, S.; Tyree, C.; Ackerman, E.; Zhang, X.; Ahn, K.; Nguyen, P.; Comer, D.; Mao, L.; Yu, C.; Pleynet, D.; Digregorio, P. J.; Velicelebi, G.; Stauderman, K. A.; Comer, W. T.; Mobley, W. C.; Li, Y. M.; Sisodia, S. S.; Tanzi, R. E.; Wagner, S. L. |
| Article Title: | Modulation of γ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimer's disease |
| 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 Aβ42 levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Aβ40 levels while concomitantly elevating levels of Aβ38 and Aβ37. 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 Aβ42; 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). © 2010 Elsevier Inc. |
| Keywords: | controlled study; human cell; nonhuman; protein domain; animal cell; mouse; animals; mice; animal tissue; cells, cultured; gene overexpression; embryo; animal experiment; animal model; protein binding; notch receptor; cell differentiation; high throughput screening; dose-response relationship, drug; transfection; mice, inbred c57bl; mice, transgenic; gene expression regulation; enzyme inhibitors; chromatin immunoprecipitation; receptors, notch; peptide fragments; rat; fluorescence resonance energy transfer; transgene; binding site; rats; antibodies; enzyme-linked immunosorbent assay; disease models, animal; analysis of variance; cadherins; alzheimer disease; protein cleavage; amyloid precursor protein secretases; gamma secretase; presenilin-1; amyloid beta protein[1-42]; amyloid beta-protein; spectrometry, mass, matrix-assisted laser desorption-ionization; cricetinae; cricetulus; amyloid beta protein; affinity chromatography; neurofibrillary tangle; senile plaque; amyloid beta-protein precursor; butyric acids; hydrocarbons, halogenated |
| Journal Title: | Neuron |
| Volume: | 67 |
| Issue: | 5 |
| ISSN: | 0896-6273 |
| Publisher: | Cell Press |
| Date Published: | 2010-09-09 |
| Start Page: | 769 |
| End Page: | 780 |
| Language: | English |
| DOI: | 10.1016/j.neuron.2010.08.018 |
| PUBMED: | 20826309 |
| PROVIDER: | scopus |
| PMCID: | PMC2947312 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 9" - "Export Date: 20 April 2011" - "CODEN: NERNE" - "Source: Scopus" |
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