Discovering mechanisms of neurodegeneration for potential therapeutic intervention
The accumulation of pathological tau is the main component of neurofibrillary tangles (NFT) in several neurodegenerative diseases, referred to as tauopathies. These diseases include some of the most common neurodegenerative diseases such as progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and certain forms of frontotemporal dementia. Alzheimer’s disease, the most common cause of dementia, is a secondary tauopathy that is accompanied by the presence of amyloid-β pathology. The two major goals in my laboratory are to understand the cellular mechanisms of neurodegeneration in tauopathies and to develop novel therapies for these diseases. We are particularly interested in studying astrocytes and neuroinflammation as they are beginning to emerge as a critical component of neurological disorders. Our goal is to understand the mechanisms that regulate reactive astrocytes and their neurotoxicity by utilizing a combination of biochemistry, molecular biology, cellular models of inflammation and mouse models of neurodegenerative diseases. We are also interested in developing immunotherapeutic approaches targeting tau the pathological protein in tauopathies. Compelling evidence from several studies, have demonstrated passive immunization using certain monoclonal antibodies against human tau are neuroprotective in mouse models of tauopathies. We have engineered a series of single-chain fragments variables (scFVs) directed against human tau that contain the variable regions of the heavy and light chains from the most promising antibody, anti-tau HJ8.5 developed in collaboration with Dr. David Holtzman at Washington University. These anti-tau scFVs serve as molecular tools for engineering immunotherapeutics optimized for tau depletion.