TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β42 Lowering by GSM-10h

Background: Cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-β (Aβ) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aβ42 peptide while avoiding deleterious activity on Notch processing. Objective: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aβ peptides to induce neurotoxicity in rat primary cortical neurons. Methods: The effect of GSM-10h on Aβ levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. Results:In cells, GSM-10h decreased levels of Aβ42 while concomitantly increasing levels of Aβ38 in the absence of effects on Aβ40 levels. In TASTPM mice, GSM-10h effectively lowered brain Aβ42 and increased brain Aβ38, with no effect on Notch signalling. Unlike Aβ42, which causes neuronal cell death, neither Aβ37 nor Aβ38 were neurotoxic. Conclusions: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.

[1]  J. D. Elliott,et al.  Pyridine-derived γ-secretase modulators. , 2011, Bioorganic & medicinal chemistry letters.

[2]  I. Hussain,et al.  Piperidine-Derived γ-Secretase Modulators. , 2010 .

[3]  I. Hussain,et al.  Piperidine-derived gamma-secretase modulators. , 2010, Bioorganic & medicinal chemistry letters.

[4]  M. Wolfe.  Inhibition and modulation of γ-secretase for Alzheimer’s disease , 2008, Neurotherapeutics.

[5]  M. Wolfe,et al.  Substrate-targeting γ-secretase modulators , 2008, Nature.

[6]  Richard M. Page,et al.  Generation of Aβ38 and Aβ42 Is Independently and Differentially Affected by Familial Alzheimer Disease-associated Presenilin Mutations and γ-Secretase Modulation* , 2008, Journal of Biological Chemistry.

[7]  B. de Strooper,et al.  1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity , 2007, Journal of Pharmacology and Experimental Therapeutics.

[8]  S. Weggen,et al.  Insensitivity to Aβ42-lowering Nonsteroidal Anti-inflammatory Drugs and γ-Secretase Inhibitors Is Common among Aggressive Presenilin-1 Mutations*♦ , 2007, Journal of Biological Chemistry.

[9]  T. Golde,et al.  Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice , 2007, BMC Neuroscience.

[10]  Dmitri A Pissarnitski.  Advances in gamma-secretase modulation. , 2007, Current opinion in drug discovery & development.

[11]  P. Jeffrey,et al.  Oral administration of a potent and selective non‐peptidic BACE‐1 inhibitor decreases β‐cleavage of amyloid precursor protein and amyloid‐β production in vivo , 2007 .

[12]  C. Haass,et al.  Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators. , 2006, Journal of medicinal chemistry.

[13]  T. Lanz,et al.  Lack of Specific Amyloid-β(1-42) Suppression by Nonsteroidal Anti-Inflammatory Drugs in Young, Plaque-Free Tg2576 Mice and in Guinea Pig Neuronal Cultures , 2005, Journal of Pharmacology and Experimental Therapeutics.

[14]  J. Richardson,et al.  Cognitive correlates of Aβ deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes , 2004, Brain Research.

[15]  Jay S. Fine,et al.  Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation* , 2004, Journal of Biological Chemistry.

[16]  W. H. Jordan,et al.  Adipsin, a Biomarker of Gastrointestinal Toxicity Mediated by a Functional γ-Secretase Inhibitor* , 2003, Journal of Biological Chemistry.

[17]  S. Weggen,et al.  Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid β42 Production by Direct Modulation of γ-Secretase Activity* , 2003, Journal of Biological Chemistry.

[18]  M. Citron,et al.  Anti-Inflammatory Drug Therapy Alters β-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease , 2003, The Journal of Neuroscience.

[19]  Pritam Das,et al.  NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo , 2003 .

[20]  L. K. Baker,et al.  Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability* , 2002, The Journal of Biological Chemistry.

[21]  Rong Wang,et al.  A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity , 2001, Nature.

[22]  K. Tomita,et al.  The bHLH Gene Hes1 Regulates Differentiation of Multiple Cell Types , 2000, Molecules and cells.

[23]  G. Weinmaster,et al.  An Activated Form of Notch Influences the Choice between CD4 and CD8 T Cell Lineages , 1996, Cell.

[24]  J. Walker,et al.  Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[25]  I. Peretto,et al.  Gamma-secretase modulation and its promise for Alzheimer's disease: a medicinal chemistry perspective. , 2008, Current topics in medicinal chemistry.

[26]  P. Jeffrey,et al.  Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo. , 2007, Journal of neurochemistry.

[27]  C. Haass,et al.  N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated γ-secretase , 2007 .

[28]  C. Haass,et al.  N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase. , 2007, Bioorganic & medicinal chemistry letters.

[29]  D. Selkoe,et al.  Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease. , 1994, Annual review of cell biology.

[30]  L. Facci,et al.  Culture and Use of Primary and Clonal Neural Cells , 1990 .

[31]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.