Genomes and Genes
Cellular signaling and Trafficking of APP Family Members
Principal Investigator: LUCIANO D'ADAMIO
Affiliation: Albert Einstein College of Medicine
Abstract: The familial Alzheimer's disease gene product amyloid Beta (ABeta) precursor protein (APP) is processed to generate ABeta which is considered to be one of the major culprits of Alzheimer's disease. APP is first processed extracellularly by the alpha- or Beta-secretase creating either a C83 or C99 membrane tether fragment, respectively, and then by the gamma-secretase in the transmembrane domain. Processing by the Beta- and gamma-secretase leads to production of ABeta as well as AID (APP Intracellular Domain) which is derived from APP's extreme carboxy terminus. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression and cellular calcium homeostasis. APP is a member of a gene family that includes the APP like molecules APLP1 and APLP2. Studies using knock out mice have demonstrated that APP, APLP1 and APLP2 have partially redundant functions as well as unique roles. Since APP signals by releasing the biologically active AID peptide, it is possible that APLP1 and APLP2 also release biologically active APP Like Intracellular Domains ALIDs due to processing by the g-secretase. The major goals of the current proposal are to characterize the signaling pathways regulated by APP, APLP1 and APLP2 processing. These studies could unveil the signaling pathways that are either common or specific and unique to each APP family member. In this context, we will also study the trafficking of APP family members in primary neurons. The transport of APP in neurons may be of great relevance to the biological function of APP in neuronal ceils and may regulate neurite growth. These studies may clarify the biological role of APP family members and have important practical applications in the development of new compounds for the cure and or prevention of Alzheimer's disease.
Funding Period: 2003-04-15 - 2009-03-31
more information: NIH RePORT
- The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta productionShuji Matsuda
Albert Einstein College of Medicine, Bronx, NY 10461, USA
J Biol Chem 280:28912-6. 2005..Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A(beta)PP processing would define dysregulation of A(beta)PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD...
- Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer diseaseSimona Arena
Proteomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Naples, Italy
Mol Cell Proteomics 5:97-113. 2006....
- BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrateShuji Matsuda
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
J Neurosci 28:8668-76. 2008..Alterations of BRI2 by gene targeting or transgenic expression regulate Abeta levels and AD pathology in mouse models of AD. Competitive inhibition of APP processing by BRI2 may provide a new approach to AD therapy and prevention...
- Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signalingDawang Zhou
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
J Alzheimers Dis 16:301-7. 2009..Our results indicate that phosphorylation of the cytoplasmic tail of AbetaPP on Tyr-682 represents a second mechanism, alternative to AbetaPP processing by secretases, that regulates AbetaPP/Fe65 downstream signaling pathways...
- BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2Shuji Matsuda
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 1046, USA
J Biol Chem 284:15815-25. 2009..Competitive inhibition of APP processing by BRI3 may provide a new approach to AD therapy and prevention...
- Generation and initial characterization of FDD knock in miceLuca Giliberto
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
PLoS ONE 4:e7900. 2009..The interaction between the two precursors, APP and BRI(2), and possibly between Abeta and ABri or ADan, could be important in influencing the rate of amyloid production or the tendency of these peptides to aggregate...