Independent Generation of A 42 and A 38 Peptide Species by -Secretase

Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine-University, D-40225 Duesseldorf, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2008; 283(25):17049-54. DOI: 10.1074/jbc.M802912200
Source: PubMed


Proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase generates the amyloid-beta (Abeta) peptides, which are principal drug targets in Alzheimer disease therapeutics. gamma-Secretase has imprecise cleavage specificity and generates the most abundant Abeta40 and Abeta42 species together with longer and shorter peptides such as Abeta38. Several mechanisms could explain the production of multiple Abeta peptides by gamma-secretase, including sequential processing of longer into shorter Abeta peptides. A novel class of gamma-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Abeta42 levels without a change in Abeta40 levels. A signature of GSMs is the concomitant increase in shorter Abeta peptides, such as Abeta38, leading to the suggestion that generation of Abeta42 and Abeta38 peptide species by gamma-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 Abeta42 reductions as compared with wild type PS1. We have now used this model system to investigate whether Abeta38 production would be similarly affected indicating coupled generation of Abeta42 and Abeta38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased Abeta38 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 Abeta peptide species. These data provide evidence that Abeta42 and Abeta38 species can be independently generated by gamma-secretase and argue against a precursor-product relationship between these peptides.

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    • "Interestingly, this shift in initial docking and production lines is also observed in four of the six PSEN1 mutants (Figure 5C and D). The fact that some FAD–PSEN1 mutations combine these two mechanisms (impaired fourth cycle and change in the product line preference) explains the direct and indirect correlations between Ab38 and Ab42 levels reported in the past (Czirr et al, 2008; Page et al, 2008). Our study thus demonstrates that FAD mutations cause qualitative changes in the Ab profiles by various mechanisms (Bentahir et al, 2006; De Strooper, 2007), and that decreased release of intracellular domains (Kelleher and Shen, 2010) is not an essential part of the AD pathogenic mechanism. "
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    ABSTRACT: The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42. Loss of ɛ-cleavage function is not generally observed among FAD mutants. On the other hand, γ-secretase inhibitors used in the clinic appear to block the initial ɛ-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (γ) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts.
    The EMBO Journal 04/2012; 31(10):2261-74. DOI:10.1038/emboj.2012.79 · 10.43 Impact Factor
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    • "sA␤PP␤ could also represent a key element between tau-and amyloidopathies. The specific fate of A␤ 38 may be related to its lower aggregation tendency when compared to A␤ 40 or A␤ 42 , as well as its distinct production pathway by the ␥ secretase [49] [50], which might be modulated by sA␤PP␤ and/or Tau. Anyway, it is quite difficult to conclude on the effect of these modifications since A␤ 38 has, to our knowledge, no specific physiological effects. "
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    ABSTRACT: To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.
    Journal of Alzheimer's disease: JAD 06/2011; 26(3):553-63. DOI:10.3233/JAD-2011-110515 · 4.15 Impact Factor
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    • "After fast axonal transport of APP to synaptic terminals [6], α- or β-secretase cleaves the protein into soluble APP (sAPP-α or sAPP-β) and C-terminal fragments (αCTFs and βCTFs) [7]. Subsequent cleavage of βCTFs (by γ-secretase) yields amyloid β (Aβ) peptides X-38, X-40 and X-42 [8]. AβX-42 is prone to deposition in amyloid plaques [9], and an association between low levels of AβX-42 in cerebrospinal fluid (CSF) and presence of amyloid plaques has been shown both in molecular imaging [5] and post-mortem histopathological studies [10]. "
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    ABSTRACT: Alzheimer's disease (AD) and cerebrovascular disease (CVD) including chronic small vessel disease of the brain (SVD) are the most frequent causes of dementia. AD is associated with metabolism of amyloid precursor protein (APP) and low levels of amyloid-beta peptide (Abeta) X-42 in the cerebrospinal fluid (CSF). CVD and SVD are established risk factors for AD, brain white matter lesions (WML) are established surrogate markers for SVD and are also associated with reduced CSF AbetaX-42.A cohort survey was performed to examine whether SVD or acute CVD affects APP metabolism and to explore a potential association between WML and APP metabolism in two groups; cognitively impaired patients, subjective and mild (SCI and MCI) and stroke patients. Through measurements of CSF APP metabolite levels in patients with a wide range of WML volumes, this study aimed to determine how SVD influences APP metabolism. Sixty-three patients were included: 37 with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI) without stroke, and 26 after acute stroke. Chronic and acute WML volume and infarct volume were determined by magnetic resonance imaging (MRI) post-scan processing, and CSF levels of alpha- and beta-cleaved soluble APP (sAPP-alpha and sAPP-beta, AbetaX-38, AbetaX-40 and AbetaX-42) were determined. The Mann-Whitney test was used to compare the patient groups. Chronic and acute WML volumes, infarct volume, age, and sex were used as predictors for CSF biomarker levels in linear regression analysis. CSF levels of sAPP-alpha and sAPP-beta were strongly correlated (r = 0.95, p < 0.001) and lower levels of these biomarkers were found in the stroke group than in the SCI/MCI group; median sAPP-alpha 499.5 vs. 698.0 ng/mL (p < 0.001), sAPP-beta 258.0 vs. 329.0 ng/mL (p < 0.005). CSF levels of sAPP-alpha, sAPP-beta, AbetaX-38, AbetaX-40 and AbetaX-42 were inversely correlated with chronic WML volume (p </= 0.005; p </= 0.01; p </= 0.01; p </= 0.05; p </= 0.05 respectively), but not with acute WML or infarct volumes. Lower CSF levels of sAPP-alpha and sAPP-beta in the stroke group than in the SCI/MCI group and an inverse correlation with chronic WML indicate that ischemia lowers the levels of CSF sAPP metabolites and suggests that APP axonal transport or metabolism may be affected in SVD of the brain.
    Cerebrospinal Fluid Research 07/2010; 7(1):10. DOI:10.1186/1743-8454-7-10 · 1.81 Impact Factor
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