The Role of p38 MAPK as a Putative Drug Target Against Alzheimer's Disease Tangle Pathology
Bruce Lamb, PhD
The Cleveland Clinic Foundation (Cleveland, OH)
July 1, 2011 to June 30, 2013
Grant Reference ID:
Role of p38 MAPK in the Microglial-Mediated Alzheimer's Disease Tau Pathology
In a recent study (published in October 7th, 2010 issue of the journal NEURON), we have identified p38 MAPK as a link between neuroinflammation, cell-autonomous to microglia, and Alzheimer's disease tau pathology. In the current study, the role of a safe, orally bioavailable and brain permeable p38 MAPK inhibitor (MW01-2-069A-SRM) in preventing tau pathology will be examined both in vitro utilizing primary neurons and in vivo utilizing a unique transgenic mouse model of tauopathy (hTau mice).
Dr. Bruce Lamb's laboratory has already shown that inflammation by a particular immune cell, called microglia, can start and accelerate tangles in cell cultures and in a transgenic mouse model of Alzheimer's disease. A protein, called p38 MAPK, is involved with this inflammation and subsequent creation of tangles. Dr. Lamb and collaborators will determine whether a drug, called 069A, will target the p38 MAPK protein and prevent tangles from forming in the brains of mice with a human form of Alzheimer's disease. Collaborators have adapted the 069A drug to enable it to be taken by mouth and get into the brain. If an experimental increase in p38 MAPK causes an increase in tangles and intervention with 069A prevents it, then a future goal would be to test this drug in a human clinical trial for treatment of Alzheimer's disease.
The overall goal of this study is to test the effects of novel, brain permeable and orally bioavailable inhibitors of p38 MAPK (an enzyme activated during brain inflammation that may be responsible for triggering the formation of Alzheimer's disease tangles) against two models of Alzheimer’s disease—inflammation-induced tau tangles in cell culture and a mouse model of human tauopathy (hTau). The p38 MAPK inhibitors are thought to prevent the toxic change in tau protein (called hyperphosphorylation), which may prevent the tangles from forming.
Normally, nerve cells treated with cell culture media derived from cultured microglia (immune cells in the brain) causes p38 MAPK activation and tau hyperphosphorylation, simulating what happens in an Alzheimer’s brain. Drs. Bhaskar’ and Lamb’s team has observed that treating these nerve cells in culture with two different types of p38 MAPK inhibitors (called Inhibitor #1 and Inhibitor #2) completely blocked the p38 MAPK activation and significantly reduced tau hyperphosphorylation. Notably, these inhibitors showed maximum effect in blocking tau phosphorylation around 90 minutes after adding microglial culture media. In the second set of studies, the team performed dose-response analysis, where neurons were treated with different concentrations of p38 MAPK inhibitors prior to adding the microglial culture media. The results suggest that maximum p38 MAPK inhibition occurred at a concentration of 0.02 µM for Inhibitor #1 and was higher for Inhibitor #2, suggesting that the former inhibitor is more potent than the latter. Finally, the team gave the two inhibitors by mouth for 14 days to aged (18 months of age or older) hTau mice (3-6 animals per group) with advanced stages of tangle pathology, similar to those that occur in human Alzheimer’s disease. Mice treated with either drug showed marked decrease in p38 MAPK activation and significant reduction in tau phosphorylation. Notably, Inhibitor #1 displayed higher efficacy than Inhibitor #2. Together, the preliminary results suggest that inhibiting p38 MAPK activation reduces tau phosphorylation both in cell culture and in animal model of tauopathy. Drs. Bhaskar’ and Lamb’s team is currently studying whether this inhibition of p38 MAPK and reduced tau pathology translates into improved cognitive function in the hTau mice.
First published on: Wednesday, July 6, 2011
Last modified on: Wednesday, June 1, 2011