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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
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.
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.
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. Journal of Neuroscience 25:1219-1225.
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 U.S.A. 103:353-358.
Deng Y, Tarassishin L, Kallhoff V, Peethumnongsin E, Wu L, Li YM, Zheng H (2006) Deletion of presenilin 1 hydrophilic loop sequence leads to impaired
gamma-secretase activity and exacerbated amyloid pathology. Journal of Neuroscience 26:3845-3854.
Wang R, Wang B, He W, Zheng H (2006) Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. Journal of
Biological Chemistry 281:15330-15336.
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 U.S.A. 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.
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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