A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Abeta-induced biomarker abnormality on cultured fibroblasts.
PKC signaling is critical for the non-toxic degradation of amyloid precursor protein (APP) and inhibition of GSK3beta, which controls phosphorylation of tau protein in Alzheimer's disease (AD). Thus the misregulation of PKC signaling could contribute to the origins of AD. Bryostatin, a potent PKC modulator, has the potential to ameliorate both the neurodegeneration and the recent memory loss associated with AD. As reported herein bryostatin and a potent synthetic analog (picolog) are found to cause stimulation of non-amyloidogenic pathways by increasing alpha-secretase activity and thus lowering the amount of toxic Abeta produced. Both bryostatin and picolog increased the secretion of the alpha-secretase product (s-APP-alpha) of APP at sub-nanomolar to nanomolar concentrations. A peripheral AD-Biomarker has previously been autopsy-validated. This Biomarker, based on bradykinin-induced differential phosphorylation of Erk1 and Erk2, has been used here to test the therapeutic efficacy both for bryostatin and picolog. Both of these PKC activators are then shown to convert the AD Erk1/2 phenotype of fibroblasts into the phenotype of "normal" control skin fibroblasts. This conversion occurred for both the abnormal Erk1/2 phenotype induced by application of Abeta(1-42) to the fibroblasts or the phenotype observed for fibroblasts of AD patients. The Abeta(1-42)-induction, and PKC modulator reversal of the AD Erk1/2 biomarker phenotype demonstrate the AD-Biomarker's potential to monitor both disease progression and treatment response. Additionally, this first demonstration of the therapeutic potential in AD of a synthetically accessible bryostatin analog warrants further preclinical advancement.
Khan
Tapan K
TK
Blanchette Rockefeller Neurosciences Institute, West Virginia University, Morgantown, 26506, USA. tapan_khan@brni-jhu.org
Nelson
Thomas J
TJ
Verma
Vishal A
VA
Wender
Paul A
PA
Alkon
Daniel L
DL
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D054713:Bryostatins / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D054713:Bryostatins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; D001920:Bradykinin