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Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding.
J Neurochem. 2004 Aug; 90(4):1005-10.JN

Abstract

Studies of metabolism of the Alzheimer amyloid precursor protein (APP) have focused much recent attention on the biology of juxta- and intra-membranous proteases. Release or 'shedding' of the large APP ectodomain can occur via one of two competing pathways, the alpha- and beta-secretase pathways, that are distinguished both by subcellular site of proteolysis and by site of cleavage within APP. The alpha-secretase pathway cleaves within the amyloidogenic Abeta domain of APP, precluding the formation of toxic amyloid aggregates. The relative utilization of the alpha- and beta-secretase pathways is controlled by the activation of certain protein phosphorylation signal transduction pathways including protein kinase C (PKC) and extracellular signal regulated protein kinase [ERK/mitogen-activated protein kinase (MAP kinase)], although the relevant substrates for phosphorylation remain obscure. Because of their apparent ability to decrease the risk for Alzheimer disease, the effects of statins (HMG CoA reductase inhibitors) on APP metabolism were studied. Statin treatment induced an APP processing phenocopy of PKC or ERK activation, raising the possibility that statin effects on APP processing might involve protein phosphorylation. In cultured neuroblastoma cells transfected with human Swedish mutant APP, atorvastatin stimulated the release of alpha-secretase-released, soluble APP (sAPPalpha). However, statin-induced stimulation of sAPPalpha release was not antagonized by inhibitors of either PKC or ERK, or by the co-expression of a dominant negative isoform of ERK (dnERK), indicating that PKC and ERK do not play key roles in mediating the effect of atorvastatin on sAPPalpha secretion. These results suggest that statins may regulate alpha-secretase activity either by altering the biophysical properties of plasma membranes or by modulating the function of as-yet unidentified protein kinases that respond to either cholesterol or to some intermediate in the cholesterol metabolic pathway. A 'phospho-proteomic' analysis of N2a cells with and without statin treatment was performed, revealing changes in the phosphorylation state of several protein kinases plausibly related to APP processing. A systematic evaluation of the possible role of these protein kinases in statin-regulated APP ectodomain shedding is underway.

Authors+Show Affiliations

Farber Institute for Neurosciences of Thomas Jefferson University, Jefferson Hospital for Neuroscience, Philadelphia, Pennsylvania 19107, USA. samgandy@earthlink.netNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15287907

Citation

Parvathy, S, et al. "Atorvastatin-induced Activation of Alzheimer's Alpha Secretase Is Resistant to Standard Inhibitors of Protein Phosphorylation-regulated Ectodomain Shedding." Journal of Neurochemistry, vol. 90, no. 4, 2004, pp. 1005-10.
Parvathy S, Ehrlich M, Pedrini S, et al. Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding. J Neurochem. 2004;90(4):1005-10.
Parvathy, S., Ehrlich, M., Pedrini, S., Diaz, N., Refolo, L., Buxbaum, J. D., Bogush, A., Petanceska, S., & Gandy, S. (2004). Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding. Journal of Neurochemistry, 90(4), 1005-10.
Parvathy S, et al. Atorvastatin-induced Activation of Alzheimer's Alpha Secretase Is Resistant to Standard Inhibitors of Protein Phosphorylation-regulated Ectodomain Shedding. J Neurochem. 2004;90(4):1005-10. PubMed PMID: 15287907.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding. AU - Parvathy,S, AU - Ehrlich,Michelle, AU - Pedrini,Steve, AU - Diaz,Nichole, AU - Refolo,Lorenzo, AU - Buxbaum,Joseph D, AU - Bogush,Alexey, AU - Petanceska,Suzana, AU - Gandy,Sam, PY - 2004/8/4/pubmed PY - 2004/10/29/medline PY - 2004/8/4/entrez SP - 1005 EP - 10 JF - Journal of neurochemistry JO - J Neurochem VL - 90 IS - 4 N2 - Studies of metabolism of the Alzheimer amyloid precursor protein (APP) have focused much recent attention on the biology of juxta- and intra-membranous proteases. Release or 'shedding' of the large APP ectodomain can occur via one of two competing pathways, the alpha- and beta-secretase pathways, that are distinguished both by subcellular site of proteolysis and by site of cleavage within APP. The alpha-secretase pathway cleaves within the amyloidogenic Abeta domain of APP, precluding the formation of toxic amyloid aggregates. The relative utilization of the alpha- and beta-secretase pathways is controlled by the activation of certain protein phosphorylation signal transduction pathways including protein kinase C (PKC) and extracellular signal regulated protein kinase [ERK/mitogen-activated protein kinase (MAP kinase)], although the relevant substrates for phosphorylation remain obscure. Because of their apparent ability to decrease the risk for Alzheimer disease, the effects of statins (HMG CoA reductase inhibitors) on APP metabolism were studied. Statin treatment induced an APP processing phenocopy of PKC or ERK activation, raising the possibility that statin effects on APP processing might involve protein phosphorylation. In cultured neuroblastoma cells transfected with human Swedish mutant APP, atorvastatin stimulated the release of alpha-secretase-released, soluble APP (sAPPalpha). However, statin-induced stimulation of sAPPalpha release was not antagonized by inhibitors of either PKC or ERK, or by the co-expression of a dominant negative isoform of ERK (dnERK), indicating that PKC and ERK do not play key roles in mediating the effect of atorvastatin on sAPPalpha secretion. These results suggest that statins may regulate alpha-secretase activity either by altering the biophysical properties of plasma membranes or by modulating the function of as-yet unidentified protein kinases that respond to either cholesterol or to some intermediate in the cholesterol metabolic pathway. A 'phospho-proteomic' analysis of N2a cells with and without statin treatment was performed, revealing changes in the phosphorylation state of several protein kinases plausibly related to APP processing. A systematic evaluation of the possible role of these protein kinases in statin-regulated APP ectodomain shedding is underway. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15287907/Atorvastatin_induced_activation_of_Alzheimer's_alpha_secretase_is_resistant_to_standard_inhibitors_of_protein_phosphorylation_regulated_ectodomain_shedding_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2004&volume=90&issue=4&spage=1005 DB - PRIME DP - Unbound Medicine ER -