Role of p38 MAPK in the Microglial-Mediated Alzheimer's Disease Tau Pathology

Bruce Lamb, PhD The Cleveland Clinic Foundation

Co-Principal Investigators

Kiran Bhaskar, Ph.D.


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).

Project Details

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.