Independent Generation of Aβ42 and Aβ38 Peptide Species by γ-Secretase*

Proteolytic processing of the amyloid precursor protein by β- and γ-secretase generates the amyloid-β (Aβ) peptides, which are principal drug targets in Alzheimer disease therapeutics. γ-Secretase has imprecise cleavage specificity and generates themostabundant Aβ40 and Aβ42 species together with longer and shorter peptides such as Aβ38. Several mechanisms could explain the production of multiple Aβ peptides by γ-secretase, including sequential processing of longer into shorter Aβ peptides. A novel class of γ-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Aβ42 levels without a change in Aβ40 levels. A signature of GSMs is the concomitant increase in shorter Aβ peptides, such as Aβ38, leading to the suggestion that generation of Aβ42 and Aβ38 peptide species by γ-secretase is coordinately regulated. However, no evidence for or against such a precursor-product relationship has been provided. We have previously shown that stable overexpression of aggressive presenilin-1 (PS1) mutations associated with early-onset familial Alzheimer disease attenuated the cellular response to GSMs, resulting in greatly diminished Aβ42 reductions as compared with wild type PS1. We have now used this model system to investigate whether Aβ38 production would be similarly affected indicating coupled generation of Aβ42 and Aβ38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased Aβ38 production to similar levels in four different PS1 mutant cell lines as compared with wild type PS1 cells. This was confirmed with the structurally divergent GSMs ibuprofen and indomethacin. Mass spectrometry analysis and high resolution urea gel electrophoresis further demonstrated that sulindac sulfide did not induce detectable compensatory changes in levels of other Aβ peptide species. These data provide evidence that Aβ42 and Aβ38 species can be independently generated by γ-secretase and argue against a precursor-product relationship between these peptides.

[1]  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.

[2]  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.

[3]  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.

[4]  Xuemin Xu,et al.  The same γ‐secretase accounts for the multiple intramembrane cleavages of APP , 2007 .

[5]  M. Wolfe.  When loss is gain: reduced presenilin proteolytic function leads to increased Aβ42/Aβ40 , 2007 .

[6]  B. Strooper.  Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. , 2007 .

[7]  T. Golde.  Disease modifying therapy for AD? 1 , 2006, Journal of neurochemistry.

[8]  S. Weggen,et al.  Selective modulation of Abeta42 production in Alzheimer's disease: non-steroidal anti-inflammatory drugs and beyond. , 2006, Current pharmaceutical design.

[9]  M. Wolfe.  The γ-Secretase Complex: Membrane-Embedded Proteolytic Ensemble , 2006 .

[10]  B. Strooper,et al.  Presenilin clinical mutations can affect γ‐secretase activity by different mechanisms , 2006, Journal of neurochemistry.

[11]  T. Golde,et al.  Anti-Aβ42– and anti-Aβ40–specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model , 2005 .

[12]  Yunzhou Dong,et al.  γ-Cleavage Is Dependent on ζ-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain* , 2005, Journal of Biological Chemistry.

[13]  Y. Ihara,et al.  Blocking the cleavage at midportion between γ‐ and ε‐sites remarkably suppresses the generation of amyloid β‐protein , 2005 .

[14]  Pritam Das,et al.  Diverse compounds mimic Alzheimer disease–causing mutations by augmenting Aβ42 production , 2005, Nature Medicine.

[15]  F. Kametani,et al.  Longer Forms of Amyloid β Protein: Implications for the Mechanism of Intramembrane Cleavage by γ-Secretase , 2005, The Journal of Neuroscience.

[16]  A. Goate,et al.  Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios , 2005, Journal of neurochemistry.

[17]  A. Nadin,et al.  Selected Non-steroidal Anti-inflammatory Drugs and Their Derivatives Target γ-Secretase at a Novel Site , 2004, Journal of Biological Chemistry.

[18]  B. Hyman,et al.  Nonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation , 2004, Nature Medicine.

[19]  Rong Wang,et al.  Purification and characterization of the human gamma-secretase complex. , 2004, Biochemistry.

[20]  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.

[21]  S. Weggen,et al.  Aβ42-lowering Nonsteroidal Anti-inflammatory Drugs Preserve Intramembrane Cleavage of the Amyloid Precursor Protein (APP) and ErbB-4 Receptor and Signaling through the APP Intracellular Domain* , 2003, Journal of Biological Chemistry.

[22]  T. Iwatsubo,et al.  Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation* , 2003, The Journal of Biological Chemistry.

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

[24]  D. Selkoe,et al.  Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease. , 1999, Biochemistry.

[25]  K. Beyreuther,et al.  Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  G. Multhaup,et al.  GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42 , 2013 .

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