Modulation of gamma-secretase reduces beta-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 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).

• Authors: Maria Z Kounnas, Anne M Danks, Soan Cheng, Curtis Tyree, Elizabeth Ackerman, Xulun Zhang, Kwangwook Ahn, Phuong Nguyen, Dan Comer, Long Mao, Chengzhi Yu, David Pleynet, Paul J Digregorio, Gonul Velicelebi, Kenneth A Stauderman, William T Comer, William C Mobley, Yue-Ming Li, Sangram S Sisodia, Rudolph E Tanzi, Steven L Wagner
• Journal: Neuron (Neuron) Vol. 67 Issue 5 Pg. 769-80 (Sep 09 2010) ISSN: 1097-4199 [Electronic] United States
• PMID: 20826309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Inc. All rights reserved.

Chemical References

• 4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Antibodies
• Butyrates
• Cadherins
• Enzyme Inhibitors
• Hydrocarbons, Halogenated
• PSEN1 protein, human
• Peptide Fragments
• Presenilin-1
• Receptors, Notch
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (genetics, metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (immunology, metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Analysis of Variance
• Animals
• Antibodies (pharmacology)
• Butyrates (pharmacology)
• Cadherins (metabolism)
• Cells, Cultured
• Cricetinae
• Cricetulus
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology)
• Enzyme-Linked Immunosorbent Assay (methods)
• Female
• Fluorescence Resonance Energy Transfer (methods)
• Gene Expression Regulation (drug effects)
• Humans
• Hydrocarbons, Halogenated (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Peptide Fragments (metabolism)
• Presenilin-1 (genetics)
• Rats
• Receptors, Notch (metabolism)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization (methods)
• Transfection (methods)