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Pharmacological evidences for DFK167-sensitive presenilin-independent gamma-secretase-like activity.
J Neurochem. 2009 Jul; 110(1):275-83.JN

Abstract

Amyloid-beta (Abeta) peptides production is thought to be a key event in the neurodegenerative process ultimately leading to Alzheimer's disease (AD) pathology. A bulk of studies concur to propose that the C-terminal moiety of Abeta is released from its precursor beta-amyloid precursor protein by a high molecular weight enzymatic complex referred to as gamma-secretase, that is composed of at least, nicastrin (NCT), Aph-1, Pen-2, and presenilins (PS) 1 or 2. They are thought to harbor the gamma-secretase catalytic activity. However, several lines of evidence suggest that additional gamma-secretase-like activities could potentially contribute to Abeta production. By means of a quenched fluorimetric substrate (JMV2660) mimicking the beta-amyloid precursor protein sequence targeted by gamma-secretase, we first show that as expected, this probe allows monitoring of an activity detectable in several cell systems including the neuronal cell line telencephalon specific murine neurons (TSM1). This activity is reduced by DFK167, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), and LY68458, three inhibitors known to functionally interact with PS. Interestingly, JMV2660 but not the unrelated peptide JMV2692, inhibits Abeta production in an in vitrogamma-secretase assay as expected from a putative substrate competitor. This activity is enhanced by PS1 and PS2 mutations known to be responsible for familial forms of AD and reduced by aspartyl mutations inactivating PS or in cells devoid of PS or NCT. However, we clearly establish that residual JMV2660-hydrolysing activity could be recovered in PS- and NCT-deficient fibroblasts and that this activity remained inhibited by DFK167. Overall, our study describes the presence of a proteolytic activity displaying gamma-secretase-like properties but independent of PS and still blocked by DFK167, suggesting that the PS-dependent complex could not be the unique gamma-secretase activity responsible for Abeta production and delineates PS-independent gamma-secretase activity as a potential additional therapeutic target to fight AD pathology.

Authors+Show Affiliations

Institut de Pharmacologie Moléculaire et Cellulaire and Institut de NeuroMédecine Moléculaire, UMR6097 CNRS/UNSA, Equipe labellisée Fondation pour la Recherche Médicale, Sophia-Antipolis, Valbonne, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19457123

Citation

Sevalle, Jean, et al. "Pharmacological Evidences for DFK167-sensitive Presenilin-independent Gamma-secretase-like Activity." Journal of Neurochemistry, vol. 110, no. 1, 2009, pp. 275-83.
Sevalle J, Ayral E, Hernandez JF, et al. Pharmacological evidences for DFK167-sensitive presenilin-independent gamma-secretase-like activity. J Neurochem. 2009;110(1):275-83.
Sevalle, J., Ayral, E., Hernandez, J. F., Martinez, J., & Checler, F. (2009). Pharmacological evidences for DFK167-sensitive presenilin-independent gamma-secretase-like activity. Journal of Neurochemistry, 110(1), 275-83. https://doi.org/10.1111/j.1471-4159.2009.06131.x
Sevalle J, et al. Pharmacological Evidences for DFK167-sensitive Presenilin-independent Gamma-secretase-like Activity. J Neurochem. 2009;110(1):275-83. PubMed PMID: 19457123.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological evidences for DFK167-sensitive presenilin-independent gamma-secretase-like activity. AU - Sevalle,Jean, AU - Ayral,Erwan, AU - Hernandez,Jean-François, AU - Martinez,Jean, AU - Checler,Frédéric, Y1 - 2009/04/29/ PY - 2009/5/22/entrez PY - 2009/5/22/pubmed PY - 2009/8/22/medline SP - 275 EP - 83 JF - Journal of neurochemistry JO - J Neurochem VL - 110 IS - 1 N2 - Amyloid-beta (Abeta) peptides production is thought to be a key event in the neurodegenerative process ultimately leading to Alzheimer's disease (AD) pathology. A bulk of studies concur to propose that the C-terminal moiety of Abeta is released from its precursor beta-amyloid precursor protein by a high molecular weight enzymatic complex referred to as gamma-secretase, that is composed of at least, nicastrin (NCT), Aph-1, Pen-2, and presenilins (PS) 1 or 2. They are thought to harbor the gamma-secretase catalytic activity. However, several lines of evidence suggest that additional gamma-secretase-like activities could potentially contribute to Abeta production. By means of a quenched fluorimetric substrate (JMV2660) mimicking the beta-amyloid precursor protein sequence targeted by gamma-secretase, we first show that as expected, this probe allows monitoring of an activity detectable in several cell systems including the neuronal cell line telencephalon specific murine neurons (TSM1). This activity is reduced by DFK167, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), and LY68458, three inhibitors known to functionally interact with PS. Interestingly, JMV2660 but not the unrelated peptide JMV2692, inhibits Abeta production in an in vitrogamma-secretase assay as expected from a putative substrate competitor. This activity is enhanced by PS1 and PS2 mutations known to be responsible for familial forms of AD and reduced by aspartyl mutations inactivating PS or in cells devoid of PS or NCT. However, we clearly establish that residual JMV2660-hydrolysing activity could be recovered in PS- and NCT-deficient fibroblasts and that this activity remained inhibited by DFK167. Overall, our study describes the presence of a proteolytic activity displaying gamma-secretase-like properties but independent of PS and still blocked by DFK167, suggesting that the PS-dependent complex could not be the unique gamma-secretase activity responsible for Abeta production and delineates PS-independent gamma-secretase activity as a potential additional therapeutic target to fight AD pathology. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/19457123/Pharmacological_evidences_for_DFK167_sensitive_presenilin_independent_gamma_secretase_like_activity_ L2 - https://doi.org/10.1111/j.1471-4159.2009.06131.x DB - PRIME DP - Unbound Medicine ER -