db Home Program in Developmental Biology BCM Home
Baylor College of Medicine
Previous Faculty List Next

Hui Zheng

Hui Zheng

E-mail: huiz@bcm.edu

Professor, Baylor College of Medicine
Director, Huffington Center on Aging

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


Molecular genetics of Alzheimer's disease

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.


Selected Publications

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. Proceedings of National Academy of Sciences USA 103:353-358.

Wang B, Yang L, Wang Z, Zheng H (2007) Amyloid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proceedings of National Academy of Sciences USA 104:14140-14145.

Kallhoff-Munoz V, Hu L, Chen X, Pautler RG, Zheng H (2008) Genetic dissection of gamma-secretase-dependent and -independent functions of presenilin in regulating neuronal cell cycle and cell death. Journal of Neuroscience 28:11421-11431.

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. Journal of Neuroscience 29:15660-15668.

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. Journal of Neuroscience 29:10788-10801.

Peethumnongsin E, Yang L, Kallhoff-Munoz V, Hu L, Takashima A, Pautler RG, Zheng H (2010) Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function. Journal of Neuroscience 30:13409-13418.

Li H, Wang Z, Wang B, Guo Q, Dolios G, Tabuchi K, Hammer RE, Sudhof TC, Wang R, Zheng H (2010) Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis. Journal of Biological Chemistry 285:30598-30605.

Li H, Wang B, Wang Z, Guo Q, Tabuchi K, Hammer RE, Sudhof TC, Zheng H (2010) Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proceedings of the National Academy of Sciences USA 107:17362-17367.

Wang B, Harrison W, Overbeek PA, Zheng H (2011) Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development. Development 138:4487-4497.

Guo Q, Li H, Gaddam SS, Justice NJ, Robertson CS, Zheng H (2012) Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives. Journal of Biological Chemistry 287:2437-2445.

Lian H, Shim DJ, Gaddam SS, Rodriguez-Rivera J, Bitner BR, Pautler RG, Robertson CS, Zheng H (2012) IΚBα deficiency in brain leads to elevated basal neuroinflammation and attenuated response following traumatic brain injury: implications for functional recovery. Molecular Neurodegeneration 7:47.


Contact Information

Hui Zheng, Ph.D.
Huffington Center on Aging
Baylor College of Medicine
One Baylor Plaza M320
Houston, Texas 77030, U.S.A.

Tel: (713) 798-1568
Fax: (713) 798-1610
E-mail: huiz@bcm.edu

Previous Faculty List Next