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PMID: 20826309 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

Neuron ·Vol. 67 ·No. 5 ·2010-09-09 ·Pages 769-80

Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, Zhang X, Ahn K, Nguyen P, Comer D, Mao L, Yu C, Pleynet D, Digregorio PJ, Velicelebi G, Stauderman KA, Comer WT, Mobley WC, Li YM, Sisodia SS, Tanzi RE, Wagner SL

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).

MeSH Terms
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
Chemicals
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
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Kounnas Maria Z
TorreyPines Therapeutics, Inc., La Jolla, CA 92037, USA.
Danks Anne M
Cheng Soan
Tyree Curtis
Ackerman Elizabeth
Zhang Xulun
Ahn Kwangwook
Nguyen Phuong
Comer Dan
Mao Long
Yu Chengzhi
Pleynet David
Digregorio Paul J
Velicelebi Gonul
Stauderman Kenneth A
Comer William T
Mobley William C
Li Yue-Ming
Sisodia Sangram S
Tanzi Rudolph E
Wagner Steven L
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2010.08.018
Published
2010-09-09
Pages
769-80
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2947312
Subset
IM
Grants
NIA NIH HHS · R01 AG026660 · United States
NIA NIH HHS · R01 AG026660-01 · United States
NCI NIH HHS · T32 CA062948 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2010.08.018 PMC Full Text View journal details
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