Tong Li, Ph.D.
Primary Appointment in Pathology
My research is focused on understanding the molecular mechanisms of neurodegenerative disorders, such as Alzheimer’s Disease (AD). My general approach is to create and characterize transgenic and knockout mouse models to study disease mechanisms and test therapeutic strategies for human diseases.
AD is characterized pathologically by neuritic amyloid plaques and neurofibrillary tangles (NFT) in the brain. Genetic and pathophysiological studies indicate that abnormal accumulation of Aβ peptides, which is generated by sequential cleavage of APP by BACE1 and γ-secretase, plays a key role in AD. We have been focusing on understanding the function of γ-secretase in AD and other diseases. By generating and characterizing mice deleted for nicastrin, Aph-1a and Aph-1c (components of γ-secretase), we have demonstrated that these proteins are essential for γ-secretase activity. In addition, we found that partial reduction of γ-secretase activity significantly decreased the Aβ amyloid burden in mice, suggesting that γ-secretase can serve as a therapeutic target for AD. Currently, we are testing the efficacy of targeting γ-secretase using γ-secretase inhibitors and modulators, and the combination approach that target both BACE1 and γ-secretase for AD therapy.
Interestingly, we also found that Nct+/- mice and Nct+/-;PS1+/- mice develop skin tumors mainly around the head and neck area, which histopathologically resemble human head and neck squamous cell carcinoma (HNSCC). These observations led us to hypothesize that γ-secretase can serve as a tumor suppressor and mice with mutation in genes encoding γ-secretase may serve as useful models for the study of human HNSCC. In supporting this view, in a recent phase III clinical trial, individuals who took a γ-secretase inhibitor (Semagacestat, Eli Lilly) for a prolonged period of time developed skin tumors that resemble those observed in our mouse models, which highlighted the importance of using animal models for preclinical studies of new therapies for human diseases. Our further study will also provide a better understanding of the mechanisms whereby γ-secretase functions as a tumor suppressor, information that will provide insight into the development of new therapeutics for the treatment of AD and its related skin cancer.
Abnormal protein aggregation is a common pathologically feature of neurodegenerative disease. We are interested in understanding the pathological functions of protein aggregations in AD, such as neuritic plaques and NFT. NFT is consisted of hyperphosphorylated tau protein, which is observed not only in AD but also in other neurodegenerative diseases, such as FTD and TBI related dementia. The relationship between Aβ and tau pathologies during AD progression remains unclear. Recently, we have generated a mutant tau transgenic mouse line, in which four-repeat domain of human tau carrying the mutation ΔK280 (Tau4R-ΔK280) was conditionally expressed. By crossbreeding Tau4R-ΔK280 mice with a model of Aβ amyloidosis, APPswe;PS1ΔE9 mice, we generated mice that develop both Aβ and Tau pathologies. Using this model, we will further evaluate the relationship between these two lesions and mechanism-based therapies targeting both Aβ and tau. This new tau transgenic mouse model will also be used in studying the mechanisms and biomarkers of TBI related dementia.
Li T, Ma G, Cai H, Price DL, Wong PC. Nicastrin is required for assembly of presenilin/γ-secretase complexes to mediate Notch signaling and for processing and trafficking of β-amyloid precursor protein in mammals. J. Neuroscience. 23(8):3272-7, 2003
Li T, Wen H, Brayton C, Laird FM, Ma G, Peng S, Placanica L, Wu TC, Crain BJ, Price DL, Eberhart, CG, and Wong PC. Moderate reduction of γ-secretase attenuates amyloid burden and limits mechanism-based liabilities J. Neuroscience, 2007 27(40):10849-59
Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, Fan X, Crain BJ, Price DL, Golde TE, Eberhart CG, Wong PC. EGFR and notch pathways participate in the tumor suppressor function of gamma -secretase. J Biol Chem. 2007, 282(44):32264–32273.
Chow VW, Savonenko, AV, Melnikova T, Kim H Price DL, Li T, and Wong PC. Modeling an anti-amyloid combination therapy for Alzheimer’s disease. Sci. Transl. Med. 2010. 2, 13ra1 PMCID:PMC2852193
Li T, Li Y, Ahn K, Price DL, Sisodia SS, Wong PC. Increased expression of PS1 is sufficient to elevate the level and activity of &gamma-secretase in vivo. Plos ONE. 2011, 6(11):e28179.