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Tong Li, Ph.D.
Assistant Professor of Pathology
Research Interests: Transgenic mouse models (Tau and TDP-43); Amyotrophic lateral sclerosis (ALS); Schizophrenia; Dementia; Traumatic brain injury (TBI); Protein aggregation; Molecular mechanisms of neurodegenerative disorders; Neuropathology; Alzheimer's disease ...read more
Dr. Tong Li is an assistant professor of pathology at the Johns Hopkins University School of Medicine. A neuropathologist, Dr. Li uses mouse models to study the molecular mechanisms behind (and test therapeutic strategies for) neurodegenerative disorders such as Alzheimer’s disease, schizophrenia, and amyotrophic lateral sclerosis (ALS).
Recently, his laboratory has developed a mouse model in which wild-type tau is converted to pathological tau in a neuritic plaque-dependent manner. His study offers novel mechanistic insight for the pathogenesis of Alzheimer's disease.
In his work with the Traumatic Brain Injury (TBI) Research Center, Dr. Li also is partnering with colleagues to create tau and TDP-43 transgenic mice. The goal is to better understand the genetic susceptibility to TBI, particularly chronic traumatic encephalopathy (CTE).
Dr. Li earned his B.A. at Jilin University in China and received his Ph.D. from the Shanghai Institute of Biochemistry.
- Assistant Professor of Pathology
Departments / Divisions
- Pathology - Neuropathology
Centers & Institutes
- B.A., Jilin University - Changchun (China) (1991)
- Ph.D., Shanghai Institute of Biochemistry - Shanghai (China) (1996)
Research & Publications
Dr. Li and his team study the molecular mechanisms behind neurodegenerative disorders such as Alzheimer’s disease (AD), schizophrenia, and amyotrophic lateral sclerosis (ALS). He creates and characterizes transgenic and knockout mouse models to research disease mechanisms and test therapeutic strategies for human diseases.
Because abnormal protein aggregation is a common pathologically feature of neurodegenerative disease, Dr. Li’s team is interested in understanding the pathological functions of protein aggregations in AD, such as neuritic plaques and neurofibrillary tangles (NFTs).
NFTs consist of hyperphosphorylated tau protein, which is observed in neurodegenerative diseases such as AD, TBI-related dementia, and frontotemporal dementia.
A major limitation in the AD field is the lack of a rodent model that faithfully reproduce the tau pathology seen in humans with AD. To address this critical unmet need, Dr. Li’s team also has generated tau transgenic mouse lines, in which four-repeat domain of human tau (Tau4R) or mutant tau carrying the mutation ΔK280 (Tau4RΔK) was conditionally expressed. By crossbreeding Tau4R mice with a model of Aß amyloidosis, APPswe;PS1ΔE9 mice, they developed a mouse model in which wild-type tau is converted into pathological tau aggregates and NFT that are propagated through neuronal circuits to drive neuron loss in a neuritic plaque-dependent manner. They show that the neuritic plaque is required but not sufficient for the pathological conversion of wild-type tau. Expression of a human tau repeat domain in mice is also insufficient to drive the pathological conversion of tau. They show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spread from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau, suggesting the value of combination therapy designed to prevent β-amyloidosis and pathological conversion of tau.
This new tau transgenic mouse model will also be used in studying the mechanisms and biomarkers of TBI-related dementia.
The team has also 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), researchers have demonstrated that these proteins are essential for γ-secretase activity.
They also found that partial reduction of γ-secretase activity significantly decreased the Aß amyloid burden in mice, suggesting that γ-secretase can serve as a therapeutic target for AD.
They now 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, Dr. Li’s team 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).
From these observations, his team hypothesized 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. They continue to study the mechanisms whereby γ-secretase functions as a tumor suppressor with hopes of developing new therapeutics for the treatment of AD and its related skin cancer.
Li T, Braunstein KE, Zhamg J, Lau A, Sibener L, Deeble C, Wong PC. "Tau repate domain facilitates pathological conversion of tau through the neuritic palque in Alzheimer's mice" Nature Communication, 2016, in press
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.
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.
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.
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, 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.
Activities & Honors
- New Scholar Award in Aging, The Ellison Medical Foundation, 2006 - 2010
- Society for Neuroscience, 2003
Videos & Media
Recent News Articles and Media Coverage
Press release: New Insights into How Alzheimer’s and Related Diseases Spread in the Brain. “New Mouse Model Provides More Comprehensive Model for Studying Alzheimer’s”. Nov 2014, 44th Annual Neuroscience Meeting, Washington, DC