Xuemin Xu

Xuemin Xu

Professor, Director of Biomedical Research Center
Biology Program
College of Arts and Sciences
Department of Biology
ST 2238


1982 B.S. in Chemistry, Jilin University, Changchun (P.R. China)

1985 M.S. in Biochemistry, Tokyo Institute of Technology, Japan

1989 PhD in Molecular Biology, Tokyo Institute of Technology, Japan

1989 Graduate Fellow, Mitsubishi Kasei Corporation Research Center,

Midori-ku Yokohama, 227 (Japan)


1990 to 1994 Research Associate, Immunology Department, The Scripps Research Institute, La Jolla, CA.

1994 to 1999 Assistant Professor, Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio

1999 to 2007 Associate Professor, Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee

2007 to 2017 Professor, Department of Biomedical and Diagnostic Sciences (formerly Department of Pathobiology), College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee

2018-present Dr. John Doran Endowed Professor in neurobiology, Biology Department, University of Texas of Permian Basin.


The Association for Overseas Technical Scholarship (Japan, 1989).

Pfizer Award for Research Excellence (2005).

The University of Tennessee Presidential Award for Research and Creative Achievement (2007).

American Health Assistance Foundation, Alzheimer's Disease Research Standard Awards (2009).

Dr. John Doran Endowed Professorship in Neurobiology (2018).

University of Texas System STAR award (2018)


Research in our laboratory focuses on the study of neurodegenerative diseases, especially Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). AD and ALS are both devastating neurodegenerative diseases for which there is currently no cure. AD and ALS are characterized by degeneration of select populations of neurons in certain regions of the brain and spinal cord, as well as the association of misfolded proteins after the loss of their natural functional conformation. These misfolded proteins adopt a new shape that renders them neurotoxic and prone to aggregation.

The amyloid plaques composed of the 40-42 residue b-Amyloid (Aβ) peptide and neurofibrillary tangles consisting of abnormal phosphorylated Tau protein are pathological hallmarks of AD. Increasing evidence shows that in addition to the well-known extracellular amyloid deposition in the parenchyma, Ab peptides accumulate inside neurons. It has been hypothesized that this initial accumulation is one of the earliest pathological events triggering a cascade leading to neurodegeneration. This is known as the amyloid hypothesis. Thus, understanding the mechanisms of Ab formation and accumulation is a central issue in AD research and is one of the foremost interests of our lab.

Aβ is produced from the amyloid precursor protein (APP) by β-secretase, which cleaves APP at the N-terminus of Aβ sequence, and γ-secretase, which cleaves APP at the C-terminus of Aβ sequence. γ-secretase has received more attention because 1) it generates the C-termini of Aβ peptides, which is important in the pathogenesis of AD because the longer Aβ species are more amyloidogenic, and 2) it cleaves within the transmembrane domain of APP. In understanding the mechanism of γ-secretase cleavage, we identified a new long Aβ species of 46 amino acids (Aβ46) and a new ζ-cleavage site at Aβ46 in addition to the known γ-cleavage site at Aβ40/42 and the ε-cleavage site at Aβ49. Moreover, our studies revealed that most of the known γ-secretase inhibitors inhibit the formation of the short Aβ40 and Aβ42, but cause an intracellular accumulation of long Aβ46. Therefore, these inhibitors are rather pharmacological poisons instead of potential therapeutic compounds.

These findings provided information vital to the development of strategies aimed at the design of γ-secretase inhibitors to prevent and treat AD. In addition, using differential inhibition strategies, our studies established that the C-terminus of Aβ is generated by a series of sequential cleavages. This model provides an answer to the long-standing research question as to how an intramembrane protease, such as γ-secretase, catalyzes peptide bond hydrolysis within the hydrophobic environment of the lipid bilayer.

g-secretase is a complex composed of four subunits, Presenilin, Nicastrin, Aph-1, and Pen-2. Our studies revealed that in addition to Presenilin, which functions as the catalytic subunit, Pen-2 is absolutely required for g-secretase activity and functions as a substrate recruiter. In contrast, Aph-1 is not absolutely required for either APP or Notch processing. The most notable finding is that Nicastrin is required for APP processing, but it is dispensable for Notch processing. These findings are important for therapeutic strategies aimed at inhibition or modulation of g-secretase activity, to reduce Ab formation without affecting vital Notch processing and signaling.

Apoptosis and mitochondrial dysfunction have been long implicated in neurodegenerative disease including AD and ALS. However, the lack of a direct molecular link between the disease-causative genes and proteins within the apoptotic cascades has cast a shadow of doubt over these notions. In this regard it is interesting that our studies identified a novel mitochondrial apoptotic protein PSAP (presenilin-associated protein) that interacts with both Presenilin and the apoptotic death receptor DR6, which has been recently implicated in the pathogenesis of ALS. Our recent studies have shown that PSAP plays a crucial role in mutant PS1 and DR6-mediated apoptosis. To further study the biological function of PSAP, our group has recently generated a PSAP-knockout mouse model. Interestingly, it was found that neurons isolated from the spinal cord of PSAP-knockout mice were resistant to apoptosis induced by nerve growth factor (NGF) withdrawal. Furthermore, using this new PSAP-knockout mouse model, a recent study of ours revealed that knockout of PSAP prevented neuromuscular junction denervation and greatly improved motor function in ALS mice. These findings might not only significantly contribute to our understanding of the molecular pathogenesis of ALS disease, but may also lead to the identification of a new therapeutic target for the treatment and prevention of ALS.

The overall goal of our research is to understand the molecular mechanisms underlying AD, ALS, and related neurodegenerative diseases and identify novel therapeutic targets for the development of treatments and prevention of these diseases.


1. Zhao, G., et al., Identification of a New Presenilin-dependent z-Cleavage Site within the Transmembrane Domain of Amyloid Precursor Protein. J. Biol. Chem., 2004. 279(49): p. 50647-50650.

2. Zhao, G., et al., g-Cleavage is dependent on z-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain. J Biol Chem, 2005. 280(45): p. 37689-97.

3. Xu, X., -Secretase Catalyzes Sequential Cleavages of the A?PP Transmembrane Domain. Journal of Alzheimer's Disease, 2009. 16(2): p. 211-224.

4. Hu, C., et al., Pen-2 and presenilin are sufficient to catalyze Notch processing. Journal of Alzheimer's disease: JAD, 2017. 56(4): p. 1263-1269.

5. Hu, C., et al., Nicastrin is required for amyloid precursor protein (APP) but not Notch processing, while anterior pharynx-defective 1 is dispensable for processing of both APP and Notch. Journal of Neurochemistry, 2016. 136(6): p. 1246-1258.

6. Zeng, L., et al., Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced g-Secretase-dependent and -independent Apoptosis, Respectively. Journal of Biological Chemistry, 2015. 290(30): p. 18269-18280.