title: 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.affiliation: TorreyPines Therapeutics, Inc., La Jolla, CA 92037, USA.
authors.forename: Maria Z
authors.initials: MZ
authors.lastname: Kounnas
authors.forename: Anne M
authors.initials: AM
authors.lastname: Danks
authors.forename: Soan
authors.initials: S
authors.lastname: Cheng
authors.forename: Curtis
authors.initials: C
authors.lastname: Tyree
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ackerman
authors.forename: Xulun
authors.initials: X
authors.lastname: Zhang
authors.forename: Kwangwook
authors.initials: K
authors.lastname: Ahn
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Dan
authors.initials: D
authors.lastname: Comer
authors.forename: Long
authors.initials: L
authors.lastname: Mao
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Yu
authors.forename: David
authors.initials: D
authors.lastname: Pleynet
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Digregorio
authors.forename: Gonul
authors.initials: G
authors.lastname: Velicelebi
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Stauderman
authors.forename: William T
authors.initials: WT
authors.lastname: Comer
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D002087:Butyrates; D015820:Cadherins; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D051880:Receptors, Notch; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases
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