Mutations in presenilin (PS1 and PS2) are linked to early onset of familial Alzheimer's disease (FAD). Presenilin is required for the processing of Notch and the b-amyloid precursor protein, molecules that play critical roles in development and AD pathogenesis respectively. In addition, PS1 associates with b-catenin, a multi-functional protein involved in Wnt signaling and cadherin/catenin-mediated cell adhesion. We reported that PS! down regulates b-catenin through this interaction. As such, loss of PS1 is associated with enhanced b-catenin signaling and tumorigenesis in mice. However, PS1 deficiency leads to simultaneous disruption of all presenilin activities and the definitive role of PS1-catenin pathway cannot be determined. Although PS1 -b-catenin interaction has been established, the role of PS2 in b-catenin regulation remains to be addressed. We recently discovered that PS2 facilitates PS1-mediated skin tumorigenesis. This calls for a need to systematically investigate the involvement of PS2 in b-catenin pathway. Directly relevant to AD, PS1 is localized at synaptic contacts and PS1 FAD mutant protein exhibits impaired b-catenin regulating activities, raising the possibility that an impaired b-catenin homeostasis may contribute to synaptic dysfunction, a hallmark intimately linked to AD dementia. The following hypotheses are formulated based on these findings: a) Presenilin-b-catenin association plays a central role in b-catenin signaling and cadherin/catenin-mediated cell adhesion in vivo. Deregulation of b-catenin is causal for loss-of-PS1-induced neoplasia and alters synaptic activity in the central nervous system; b) PS1FAD mutation leads defective b-catenin regulation and synaptic dysfunction; c) PS1 and PS2 cooperate to negatively regulate b-catenin. This application is aimed at testing these hypotheses using a novel biological tool we recently created: The PS1 knock-in mice with specific deletion of b-catenin interaction. This allele genetically separates the two important activities PS1 mediates, namely Notch and b-catenin, under in vivo physiological conditions, thus allowing us to definitely determine the role of PS1 -b-catenin pathway. The availability of the PS1M146V FAD knock-in mice makes it feasible to evaluate the effect of FAD mutation on b-catenin pathway. Further, the mechanisms of PS2 in b-catenin regulation will be investigated. The proposed study will lead to a comprehensive understanding of the molecular mechanisms of presenilin and the effect of FAD mutation on b-catenin regulation, tumorigenesis and synaptic formation and maintenance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021141-02
Application #
6649686
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$357,438
Indirect Cost
Name
Baylor College of Medicine
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Kallhoff-Munoz, Verena; Hu, Lingyun; Chen, Xiaoli et al. (2008) Genetic dissection of gamma-secretase-dependent and -independent functions of presenilin in regulating neuronal cell cycle and cell death. J Neurosci 28:11421-31
Wang, Baiping; Yang, Li; Wang, Zilai et al. (2007) Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc Natl Acad Sci U S A 104:14140-5
Wang, Runsheng; Wang, Baiping; He, Wanxia et al. (2006) Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. J Biol Chem 281:15330-6
Deng, Yu; Tarassishin, Leonid; Kallhoff, Verena et al. (2006) Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology. J Neurosci 26:3845-54
Wang, Pei; Yang, Guang; Mosier, Dennis R et al. (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci 25:1219-25