Molecular genetics of Alzheimer's disease
Alzheimer's disease (AD) is a leading cause of senile dementia characterized by the loss of neurons and
deposition of beta-amyloid plaques in the brain of affected individuals. 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 is interested in AD research using mouse genetic approach. We focus on two basic questions: One is
to understand the physiological functions of AD associated molecules and the other is to determine the pathogenic effects of
the disease-causing mutations. In the past, we have generated mice deficient for APP, PS1 and PS2. We recently identified an
important role of APP family in the differentiation of neuromuscular synapses. Determining the molecular mechanisms underlying
the APP activity in peripheral and central nervous systems consists of one of the research topics ongoing in the laboratory.
Presenilins has been shown to possess multiple biological activities. They are essential for proteolytic processing of
APP to generate Ab peptides, an event linked to AD pathogenesis. Through similar mechanisms, PS are required to cleave and
activate Notch, molecules that play critical roles in cell fate determination. Using an extensive panel of transgenic, gene
knockout and knock-in mice, we uncovered two novel functions of PS in vivo: kidney organogenesis and tumorigenesis. We also
generated experimental data to support a partial loss-of-function mechanism by the disease causing mutations. Dissecting
multiple PS-mediated pathways consist of major research efforts of the laboratory. We are complementing the in vivo genetic
approach with in vitro pharmacological manipulation using highly potent PS inhibitors. Overall, our investigation will lead
to better understanding of AD pathophysiology and allow discovery of novel therapeutic strategies.
Selected Publications
Qian S, Jiang P, Guan XM, Singh G, Trumbauer ME, Yu H, Chen HY, Van de Ploeg LH, Zheng H (1998) Mutant human
presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression.
Neuron 20:611-617.
Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H (2001) Loss of presenilin 1 is associated
with enhanced β-catenin signaling and skin tumorigenesis. Proceedings of the National Academy of Sciences U.S.A.
98:10863-10868.
Dineley KT, Xia X, Bui D, Sweatt JD, Zheng H (2002) Accelerated plaque accumulation, associative learning deficits,
and up-regulation of α7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid
precursor proteins. Journal of Biological Chemistry 277:22768-22780.
Xia X, Wang P, Sun X, Soriano S, Shum WK, Yamaguchi H, Trumbauer ME, Takashima A, Koo EH, 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. Proceedings of the National Academy of Sciences U.S.A. 99:8760-8765.
Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH (2002) Presenilin couples the paired
phosphorylation of β-catenin independent of axin: implications for β-catenin activation in tumorigenesis. Cell
110:751-762.
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.
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
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