The Immunobiology and Immunotherapy Laboratory focuses on studies of immunotherapy targeting tau and development of strategies to prevent and treat Alzheimer’s disease alone, Alzheimer’s disease (AD) in Down syndrome (DS), and other tauopathies.
Tau is predominantly a soluble cytoplasmic protein that stabilizes microtubules in physiological conditions. Under pathological conditions, tau is abnormally hyperphosphorylated and aggregated as neurofibrillary tangles, which are involved in AD, DS, and other tauopathies. Furthermore, the abnormally hyperphosphorylated tau can be released into the extracellular space from the affected neurons and serves as the seeds for the propagation of tau pathology in the brain, which provides a therapeutic target for tau immunotherapy to block the propagation of tau pathology in brain.
Current projects are addressing i) whether immunotherapy with tau antibodies 43D against tau 6-18, and 77E9 against tau 184-195 can reverse the cognitive impairments, prevent the development of tau pathology, and even decrease the tau pathology, in transgenic mouse models; ii) whether tau immunotherapy can block the propagation of tau pathology and ameliorate behavioral performance in animal models; and iii) whether tau immunotherapy can prevent and/or reverse age-associated cognitive impairment during aging.
In the future, our lab will investigate i) the characteristics of extracellular tau in cerebrospinal fluid (CSF); ii) the role of extracellular tau in the development and spread of tau pathology; and iii) the role of extracellular tau in neuronal hyperactivity during aging and age-associated cognitive impairment. Findings from current and future projects in our lab will help us develop more specific approaches to preventing and/or treating AD and other neurodegenerative diseases.
We have found that i) immunization with both tau antibodies 43D and 77E9 decreases tau pathology and improves cognitive functions in the 3xTg-AD mouse model; ii) immunization with tau antibody 43D inhibits the seeding activity of hyperphosphorylated tau from AD brain and blocks the spread of tau pathology templated by hyperphosphorylated tau in vivo; and iii) immunization with tau antibody 77E9 improves behavioral performance in aged mice. These findings suggest that passive immunization targeting tau 6–18 may present a disease-modifying approach to AD and related tauopathies.