Hui Zheng, Ph.D.
Professor of Molecular and Human Genetics
Professor, Departments of Molecular & Cellular Biology and Neuroscience; Programs in Integrative Molecular and Biomedical Sciences; Developmental Biology; and Translational Biology & Molecular Medicine; Huffington Center on Aging
Director, Huffington Center on Aging
B.S., Peking University, 1984
Ph.D., Baylor College of Medicine, 1990
Alzheimer's disease (AD) is a leading cause of senile dementia with the pathological hallmarks of beta-amyloid plaques, neurofibrillary tangles, synaptic dysfunction and neuronal cell loss. The major components of the plaques are 40 to 42 amino acid peptides (Aβ) derived from the amyloid precursor protein (APP). Two classes of genes have been identified that are genetically linked to AD: APP and presenilins. Mutations in these genes lead to dominant inheritance of familial AD (FAD), establishing a central role of APP and presenilins (PS) in AD pathogenesis. My laboratory is interested in understanding the pathophysiology of APP and PS and developing a mouse model that recapitulates AD pathogenic process.
Using APP loss-of-function mutants, we identified an essential role of the APP proteins in neuromuscular synapse development. By creating an APP conditional allele, we found that APP functions as a synaptic adhesion protein and that pre- and postsynaptic APP cooperate to regulate synaptic structure and function. We propose that impaired APP trans-synaptic activity may lead to synaptic dysfunction and AD dementia. Our current research is directed at identifying the upstream modulators and downstream targets of APP-mediated synaptic adhesion pathway and delineating the pathogenic effects of APP FAD mutation and Aβ.
PS are essential for proteolytic processing of APP to generate Aβ peptides. As such, PS inhibitors are actively pursued as a potential therapy for amyloid intervention. However, through similar mechanisms, PS is required to cleave and activate Notch and has been implicated in processing other type I membrane proteins. Taking advantage of the extensive panel of PS mutant mice and our novel PS rescue system, we uncovered various physiological functions of PS and established a partial loss-of-function mechanism by the PS FAD mutations. These findings provide important therapeutic insights toward the development of PS inhibitors.
The current available AD mouse models are based on APP overexpression, which causes serious confounding effects and the animals do not exhibit classic AD neuropathology beyond amyloid plaques. To overcome these major limitations, we have created a series of humanized knock-in mouse models which develop amyloid or neurofibrillary pathologies either individually or both combined. These unique second-generation AD mouse models allow us to dissect pathogenic effects downstream of amyloid, tangles, or both. Understanding the cascade of events leading to full AD pathology at molecular, neuroanatomical, electrophysiological and behavioral levels forms the major focus of our current research. Our goal is to identify early markers and critical pathways for AD diagnosis and intervention through these lines of investigations.
A neuronal/HEK293 mixed culture assay showing that expressing APP, similar to the neuroligin (NL) positive control, in non-neuronal cells (green) induces excitatory synaptic puncta (vGLUT-positive, red) formation, demonstrating that APP is a synaptic adhesion protein.
- Wang B, Harrison W, Overbeek P, Zheng H (2011). Transposon mutagenesis with coat color genotyping identifies an essential role of SKOR2 in sonic hedgehog signaling and cerebellum development. Development 138(20): 4487-97. PubMed PMID: 21937600
- Peethumnongsin E, Yang L, Kallhoff-Muñoz V, Hu L, Takashima A, Pautler RG, Zheng H (2010). Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function. J. Neurosci. 30(40): 13409-18. PubMed PMID: 20926667
- Li H, Wang B, Wang Z, Guo Q, Tabuchi K, Hammer RE, Südhof TC, Zheng H (2010). Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc. Natl. Acad. Sci. U S A 107(40): 17362-7. PubMed PMID: 20855613
- Li H, Wang Z, Wang B, Guo Q, Dolios G, Tabuchi K, Hammer RE, Südhof TC, Wang R, Zheng H (2010). Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis. J. Biol. Chem. 285(40): 30598-605. PubMed PMID: 20693289
- Yang L, Wang Z, Wang B, Justice NJ, Zheng H (2009). Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J. Neurosci. 29(50): 15660-8. PubMed PMID: 20016080
- Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H (2009). Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J. Neurosci. 29(35): 10788-801. PubMed PMID: 19726636
- Kallhoff-Munoz V, Hu L, Chen X, Pautler RG, Zheng H (2008). Genetic dissection of γ-secretase-dependent and -independent functions of presenilin in regulating neuronal cell cycle and cell death. J. Neurosci. 28(44): 11421-31. PubMed PMID: 18971484
- Wang B, Yang L, Wang Z, Zheng H (2007). Amyloid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc. Natl. Acad. Sci. U S A 104(35): 14140-5. PubMed PMID: 17709753
- Wang R, Wang B, He W, Zheng H (2006). Wild-type presenilin protects against Alzheimer’s disease mutation-induced amyloid pathology. J. Biol. Chem. 281(22): 15330-6. PubMed PMID: 16574645
- Deng Y, Tarassishin L, Kallhoff V, Peethumnongsin E, Wu L, Li Y, Zheng H (2006). Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology. J. Neurosci. 26(14): 3845-54. PubMed PMID: 16597739
Awards and Honors
2007-2008: Chair, NIA-N Review Committee, NIH/NIA
2004-2006: Zenith Award, Alzheimer’s Association
2003-2007: Member, Neuroscience of Aging (NIA-N) Review Committee, NIH/NIA
2000-2004: New Scholars Award, Ellison Medical Foundation
Hui Zheng, Ph.D.
Huffington Center on Aging
Baylor College of Medicine
One Baylor Plaza, MS BCM230
Houston, TX 77030, U.S.A.