Baylor College of Medicine
Huffington Center on Aging
Huffington Foundation Endowed Chair in Aging
Baylor College of Medicine
Houston, Texas, United States


BS from Peking University
PhD from Baylor College Of Medicine

Professional Interests

  • Molecular genetics of Alzheimer’s disease

Professional Statement

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