Post-transcriptional Contribution of a cAMP-dependent Pathway to the Formation of Alpha- And beta/gamma-secretases-derived Products of Beta APP Maturation in Human Cells Expressing Wild-Type and Swedish Mutated Beta APP

Mol Med. 1998 Nov;4(11):715-23.

Abstract

Background: The physiopathological maturation of the beta-amyloid precursor protein can be modulated by effectors targeting a protein kinase C-dependent pathway. These agents increase the recovery of APP alpha, the physiological alpha-secretase-derived product of beta APP processing, and concomittantly lower the production of the pathogenic beta/gamma-secretase-derived A beta fragment.

Methods: We set up stably transfected HEK293 cells expressing wild-type or Swedish mutated beta APP. By combined metabolic labeling and/or immunoprecipitation procedures, we assessed the effect of various cAMP effectors on the production of the beta APP maturation products A beta 40, A beta 42, APP alpha, and its C-terminal counterpart.

Results: We show here that the cAMP-dependent protein kinase (PKA) effectors, dibutyryl-cAMP (dBut-cAMP) and forskolin, but not the inactive analog dideoxyforskolin, enhance the secretion of APP alpha and the intracellular production of its C-terminal counterpart (p10) in stably transfected HEK293 cells. The above agonists also drastically increase both A beta 40 and A beta 42 secretions and intracellular A beta recovery. The same influence was observed with HEK293 cells overexpressing the Swedish mutated beta APP. We attempted to delineate the relative contribution of transcriptional and post-transcriptional events in the cAMP-mediated response. We show here that the dBut-cAMP and forskolin-induced increase of APP alpha and A beta s secretions is not prevented by the transcription inhibitor actinomycin D.

Conclusion: Our data suggest a major contribution of post-transcriptional events in the cAMP-dependent effect on beta APP maturation. It appears likely that cAMP triggers the PKA-dependent phosphorylation of a protein involved in beta APP maturation and occurring upstream to alpha- and beta/gamma-secretase cleavages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases
  • Bucladesine / pharmacology
  • Cell Line
  • Colforsin / pharmacology
  • Cyclic AMP / agonists
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dactinomycin / pharmacology
  • Endopeptidases / metabolism*
  • Humans
  • Mutation*
  • Protein Kinase C / metabolism
  • Protein Processing, Post-Translational / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transfection

Substances

  • Amyloid beta-Protein Precursor
  • RNA, Messenger
  • Dactinomycin
  • Colforsin
  • Bucladesine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human