Abstract

The Familial Alzheimer's disease gene product Amyloid beta Precursor Protein (APP) undergoes extensive processing. APP cleavage by secretases has been studied in great detail because it generates Abeta peptides that are implicated in the pathogenesis of Alzheimer's disease. Recent data indicate that the intracellular domain of APP (AID), released together with Abeta, has signaling functions. AID can induce cell death, plays a role in the regulation of gene transcription and regulates calcium release from endoplasmic reticulum stores. We have found that AID can repress Notch-dependent transcription and that this restraint may be mediated by the interaction of AID with the Notch inhibitors Numb/Numblike (Nbl). Numb has also been involved in receptors endocytosis and endocytosis of APP is known to regulate APP processing. Based on these findings, we hypothesize that Numb/Nbl proteins mediate the inhibitory effect of AID on Notch signaling and regulate APP endocytosis and processing. In this application, we propose to study the role of Numb/Nbl proteins in inhibition of Notch by AID, in APP endocytosis and APP processing. Aside for their relevance to the biology of APP. these studies may have implications pertinent to the therapy and pathology of Alzheimer's disease. Drugs designed to lower Abeta production might also alter the levels of AID. Therefore a clear understanding of the biological functions of AID may help in predicting and preventing toxic effects due to alterations in AID production by these inhibitors. Furthermore, inhibition of Notch signaling by AID might accelerate the neurodegenerative process of Alzheimer's disease by enhancing synapse loss, neurite dystrophy and neuronal degeneration. Lastly, regulation of APP endocytosis and processing by Numb/Nbl proteins might provide potential new targets for compounds aimed to reduce Abeta production.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021588-02
Application #
6799944
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, Stephen D
Project Start
2003-09-15
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$292,250
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Matsuda, Shuji; Matsuda, Yukiko; Snapp, Erik L et al. (2011) Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles. Neurobiol Aging 32:1400-8
Giliberto, Luca; d'Abramo, Cristina; Acker, Christopher Michael et al. (2010) Transgenic expression of the amyloid-beta precursor protein-intracellular domain does not induce Alzheimer's Disease-like traits in vivo. PLoS One 5:e11609
Matsuda, Shuji; Matsuda, Yukiko; D'Adamio, Luciano (2009) BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2. J Biol Chem 284:15815-25
Giliberto, Luca; Matsuda, Shuji; Vidal, Ruben et al. (2009) Generation and initial characterization of FDD knock in mice. PLoS One 4:e7900
Tamayev, Robert; Zhou, Dawang; D'Adamio, Luciano (2009) The interactome of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol Neurodegener 4:28
Zhou, Dawang; Zambrano, Nicola; Russo, Tommaso et al. (2009) Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signaling. J Alzheimers Dis 16:301-7
Matsuda, Shuji; Giliberto, Luca; Matsuda, Yukiko et al. (2008) BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate. J Neurosci 28:8668-76
D'Ambrosio, Chiara; Arena, Simona; Fulcoli, Gabriella et al. (2006) Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease. Mol Cell Proteomics 5:97-113
Matsuda, Shuji; Giliberto, Luca; Matsuda, Yukiko et al. (2005) The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. J Biol Chem 280:28912-6
Ghersi, Enrico; Noviello, Cristiana; D'Adamio, Luciano (2004) Amyloid-beta protein precursor (AbetaPP) intracellular domain-associated protein-1 proteins bind to AbetaPP and modulate its processing in an isoform-specific manner. J Biol Chem 279:49105-12

Showing the most recent 10 out of 11 publications