Professor, Departments of Molecular and Human Genetics, Molecular & Cellular Biology, and Neuroscience; Huffington Center on Aging; Programs in Cell & Molecular Biology and Developmental Biology

B.S., Peking University, 1984
Ph.D., Baylor College of Medicine, 1990

RESEARCH INTERESTS:
Alzheimer's disease (AD) is the leading cause of senile dementia characterized by the beta-amyloid plaque deposition, synaptic dysfunction and loss of neurons, in particular the basal forebrain cholinergic neurons. The major components of the plaques are 40 to 42 amino acid peptides (Ab) derived from proteolytic processing of the amyloid precursor protein (APP). Two classes of genes have been identified that are genetically linked to early onset of AD: APP and presenilins (PS1 and PS2). Mutations in these genes lead to dominant inheritance of familial Alzheimer's disease (FAD) and are associated with accelerated plaque deposition.

My laboratory has a long-standing interest in AD research using mouse genetics approach. Because of the critical roles of APP and presenilins in AD pathogenesis, our effort has been focused on investigating the physiological functions of APP and presenilins and elucidating the pathogenic mechanisms of the disease-causing mutations. Using the peripheral cholinergic synapse neuromuscular junction (NMJ) as a model system, we identified an essential role of the APP family of proteins in regulating synaptic vesicle availability and synaptic transmission. We recently discovered that it is likely mediated by its regulation of the high affinity choline transporter CHT, a molecule that plays rate-limiting roles in cholinergic neurotransmission, and this activity appears to require APP expression in both pre- and postsynaptic compartments and applies to both NMJ and basal forebrain cholinergic neurons. This finding implies that impaired APP function may directly contribute to cholinergic neuronal vulnerability and AD pathogenesis. Current and future work is directed at deciphering the mechanisms of APP in various neuronal circuitries and investigating the effect of the pathogenic mutations.

Presenilins (PS) are essential for proteolytic processing of APP to generate Ab peptides. As such, PS inhibitors are being actively pursued as a potential therapeutic approach for amyloid intervention and AD treatment. Through similar mechanisms, PS is required to cleave and activate Notch and has been implicated in processing of other type I membrane proteins. Taking advantage of the extensive panel of PS transgenic, gene knockout and knockin mice and our novel PS “rescue” system, we uncovered various novel functions of PS in vivo, including tumorigenesis, kidney organogenesis, and pigmentation. Importantly, we reveal a physiological role of PS in intracellular protein trafficking and establish a partial loss-of-function mechanism by the PS1 FAD mutations. Our follow-up studies support a partial loss-of-function as the underlying mechanism for accelerated plaque deposition as well. We are interested in establishing the relationship between PS-dependent protein processing and intracellular trafficking. These questions are critically important to understand not only PS biology but also AD pathogenesis in general.

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SELECTED PUBLICATIONS:
1. 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. USA 104: 14140-14145.

2. 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: 15330-15336.

3. 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: 3845-3854.

4. Wang R, Tang P, Wang P, Boissy RE, 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.

5. Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H (2005). Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-like protein 2. J. Neurosci. 25: 1219-1225.

6. Wang P, Pereira FA, Beasley D, Zheng H (2003). Presenilins are required for the formation of comma- and S-shaped bodies during nephrogenesis. Development 130: 5019-5029.

7. Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH (2002). A Wnt-autonomous b-catenin pool is dependent on presenilin activity for degradation: Implications for b-catenin activation in tumorigenesis. Cell 110: 751-762.

8. Xia X, Wang P, Sun X, Soriano S, Shum WK, Trumbauer ME, Takashima A, Koo EH, Zheng H (2002). The aspartate-257 of presenilin 1 is indispensable for mouse development and production of b-amyloid peptides through b-catenin independent mechanisms. Proc. Natl. Acad. Sci. USA 99: 8760-8765.

9. Xia X, Qian S, Soriano S, Wu Y, Fletcher A, Wang XJ, Koo EH, Wu X, Zheng H (2001). Loss of presenilin 1 is associated with enhanced b-catenin signaling and skin tumorigenesis. Proc. Natl. Acad. Sci. USA 98: 10863-10868.

For more publications, see listing on Pub Med.

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Telephone: 713-798-1568
Fax: 713-798-1610
E-mail:

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