A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses A beta-induced biomarker abnormality on cultured fibroblasts

作者：Khan Tapan K^*; Nelson Thomas J; Verma Vishal A; Wender Paul A; Alkon Daniel L

来源：Neurobiology of Disease, 2009, 34(2): 332-339.

DOI：10.1016/j.nbd.2009.02.003

• Alzheimer's disease drug efficacy
• A beta
• Bryostatin
• alpha-Secretase
• Biomarker
• PKC
• Skin fibroblasts
• Erk
• Synthetic analog of bryostatin

PKC signaling is critical for the non-toxic degradation of amyloid precursor protein (APP) and inhibition of GSK3 beta, 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 A beta 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 A beta(1-42) to the fibroblasts or the phenotype observed for fibroblasts of AD patients. The A beta(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.

• 出版日期2009-5