A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts
PKC signaling is critical for the non-toxic degradation of amyloid precursor protein (APP) and inhibition of GSK3β, 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...
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doaj-c1419f51a6ac4138ba37e53ec0c61aa12021-03-20T04:57:13ZengElsevierNeurobiology of Disease1095-953X2009-05-01342332339A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblastsTapan K. Khan0Thomas J. Nelson1Vishal A. Verma2Paul A. Wender3Daniel L. Alkon4Blanchette Rockefeller Neurosciences Institute, West Virginia University, School of Medicine, Morgantown, WV 26506, USA; Corresponding author. Fax: +1 301 294 7007.Blanchette Rockefeller Neurosciences Institute, West Virginia University, School of Medicine, Morgantown, WV 26506, USADepartment of Chemistry, Stanford University, Stanford, CA 94305, USADepartment of Chemistry, Stanford University, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USABlanchette Rockefeller Neurosciences Institute, West Virginia University, School of Medicine, Morgantown, WV 26506, USA; Department of Neurology, West Virginia University, School of Medicine, Robert C. Byrd Health Science Center, PO Box 9100, Morgantown, WV 26506, USAPKC signaling is critical for the non-toxic degradation of amyloid precursor protein (APP) and inhibition of GSK3β, 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 α-secretase activity and thus lowering the amount of toxic Aβ produced. Both bryostatin and picolog increased the secretion of the α-secretase product (s-APP-α) 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 Aβ1–42 to the fibroblasts or the phenotype observed for fibroblasts of AD patients. The Aβ1–42-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.http://www.sciencedirect.com/science/article/pii/S0969996109000308Alzheimer's disease drug efficacyAβBryostatinα-SecretaseBiomarkerPKC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tapan K. Khan Thomas J. Nelson Vishal A. Verma Paul A. Wender Daniel L. Alkon |
spellingShingle |
Tapan K. Khan Thomas J. Nelson Vishal A. Verma Paul A. Wender Daniel L. Alkon A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts Neurobiology of Disease Alzheimer's disease drug efficacy Aβ Bryostatin α-Secretase Biomarker PKC |
author_facet |
Tapan K. Khan Thomas J. Nelson Vishal A. Verma Paul A. Wender Daniel L. Alkon |
author_sort |
Tapan K. Khan |
title |
A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts |
title_short |
A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts |
title_full |
A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts |
title_fullStr |
A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts |
title_full_unstemmed |
A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts |
title_sort |
cellular model of alzheimer's disease therapeutic efficacy: pkc activation reverses aβ-induced biomarker abnormality on cultured fibroblasts |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2009-05-01 |
description |
PKC signaling is critical for the non-toxic degradation of amyloid precursor protein (APP) and inhibition of GSK3β, 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 α-secretase activity and thus lowering the amount of toxic Aβ produced. Both bryostatin and picolog increased the secretion of the α-secretase product (s-APP-α) 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 Aβ1–42 to the fibroblasts or the phenotype observed for fibroblasts of AD patients. The Aβ1–42-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. |
topic |
Alzheimer's disease drug efficacy Aβ Bryostatin α-Secretase Biomarker PKC |
url |
http://www.sciencedirect.com/science/article/pii/S0969996109000308 |
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