Hui Zheng, Ph.D.
Departments of Molecular Human Genetics, Molecular and Cellular Biology and Neuroscience
Ph.D.: Baylor College of Medicine, Houston
Postdoctoral training: Baylor College of Medicine, Houston
Pathophysiology of Alzheimer’s Disease Using Mouse and Cellular Models
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.
Baylor College of Medicine
One Baylor Plaza, Alkek N710
Houston, TX 77030
- Yang L, Wang Z, Wang B, Justice N and Zheng H. (2009). Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J. Neurosci., in press.
- Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z and Zheng H. (2009). Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J. Neurosci., 29:10788-10801.
- Kallhoff-Munoz V, Hu L, Chen X, Pautler RG and Zheng H. (2008). Genetic dissection of γ-secretase-dependent and -independent functions of presenilin in regulating neuronal cell cycle and cell death. J. Neurosci., 28:11421-11431.
- Wang B, Yang L, Wang Z and Zheng H. (2007). Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc. Natl. Acad. Sci. USA, 104: 14140-14145.
- Wang R, Wang B, He W and Zheng H. (2006). Wild-type presenilin protects against Alzheimer’s disease mutation-induced amyloid pathology. J. Biol. Chem., 281: 15330-15336.
- Wang R, Tang P, Wang P, Boissy RE and Zheng H. (2006). Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer’s disease mutation. Proc. Natl. Acad. Sci. USA 103: 353-358.
- Deng Y, Tarassishin L, Kallhoff V, Peethumnongsin E, Wu L, Li Y and Zheng H. (2006). Deletion of presenilin 1 hydrophilic loop sequence leads to impaired γ-secretase activity and exacerbated amyloid pathology. J. Neurosci. 26:3845-3854.
- Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong Y-D, Zhao N-M, Dominguez B, Lee K-F, Gan W-B and Zheng H. (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-like protein 2. J. Neurosci. 25: 1219-1225.
- Wang P, Pereira FA, Beasley D and Zheng H. (2003). Presenilins are required for the formation of comma- and S-shaped bodies during nephrogenesis. Development 130: 5019-5029.
- Xia X, Wang P, Sun X, Soriano S, Shum W-K, Trumbauer ME, Takashima A, Koo EH and Zheng H. (2002). The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-catenin independent mechanisms. Proc. Natl. Acad. Sci. USA 99: 8760-8765.