Despite clear genetic evidence linking the beta-amyloid precursor protein (APP) to familial Alzheimer's disease (AD), the physiological functions of APP remain ill-defined. Our previous work suggests that APP plays a role in neddylation that activates Cullin ubiquitin ligase. In preliminary data, we show that APP modulated Cullin5 levels and mutant APPs caused excessive Cullin5 degradation. We found that downregulation of the endogenous APP in primary neurons resulted in less Cullin5 turnover. We further demonstrated that more APP knockout CA1 pyramidal cells have Cullin5 expression than the wild type counterparts. These data strongly suggest that APP modulates Cullin5 ligase activity under physiological conditions, and further suggest that increased APP gene dosage or APP mutations may impair Cullin5 ligase functions by increasing its turnover rate and leading to decreased clearance of signaling molecules and neuronal dysfunction. We also discovered that inactivation of the ubiquitin-activating enzyme E1 resulted in decreased levels of APP. Furthermore, E1 co-precipitated with APP in mouse brain homogenates. These data suggest that E1 may affect APP processing by binding to APP. In this application, we hypothesize that APP is downstream of the ubiquitin- activating enzyme E1 but upstream of the ubiquitin ligase Cullin5, thus playing an important physiological function in the clearance of signaling molecules such as tyrosine kinases. This hypothesis will be tested by four inter-related Specific Aims:
Aim 1, Determine if APP regulates Cullin5 neddylation and function via BP1;
Aim 2, Elucidate how APPswe destabilizes Cullin5;
Aim 3, Determine if E1 activation increases amyloid genesis;
Aim 4, Determine if Presenilin mediates Cullin5 turnover and activation. Successful completion of this project will establish APP as an important component of the ubiquitination pathway. Therefore, the results from testing this hypothesis will provide a new understanding of APP functions/dysfunctions, which may reveal targets for disease interventions and biomarker discoveries.

Public Health Relevance

This project has the potential for discovering molecular mechanisms invaluable for developing rational disease intervention strategies and or biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034980-02
Application #
8061652
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$200,001
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Chen, Y; Neve, Rn; Zheng, H et al. (2014) Cycle on Wheels: Is APP Key to the AppBp1 Pathway? Austin Alzheimers Parkinsons Dis 1:
Chen, Yuzhi; Neve, Rachael L; Liu, Helena (2012) Neddylation dysfunction in Alzheimer's disease. J Cell Mol Med 16:2583-91
Liu, Helio C; Enikolopov, Grigori; Chen, Yuzhi (2012) Cul4B regulates neural progenitor cell growth. BMC Neurosci 13:112
Mao, Xianrong R; Moerman-Herzog, Andrea M; Chen, Yuzhi et al. (2009) Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors. J Neuroinflammation 6:16