Intensive research by many laboratories, including work performed under this grant, has advanced the hypothesis that altered processing of the 6-amyloid precursor protein (APP) or decreased clearance of its amyloid beta-peptide (AlphaBeta) fragment are critical pathogenic events in Alzheimer's disease. Nevertheless, despite a wealth of reports about in vitro and in vivo activities of the precursor and its derivitives, the fundamental physiological function of APP has not been established. Based on recent studies in our and other laboratories and extensive preliminary data, we propose to elucidate systematically the function of APP and the molecular mechanism by which it accomplishes this function. The central hypothesis motivating this proposal is that the remarkably similar proteolytic processing of APP and the Notch receptors suggests that APP is itself a cell-surface receptor with a cognate ligand, the binding of which enables the release of the cytoplasmic domain (AICD) to the nucleus to activate specific genes. Based on substantial experience in APP processing and membrane protein biology obtained during the past 24 years of this grant, we will carry out 4 interrelated Aims: 1. to purify, identify and characterize a specific protein ligand(s) for the APP ectodomain;2. to localize the APP intracellular domain (AICD) to the nucleus and study its stabilization and activites there;3. to assess the phenotypic consequences, including for APP processing and intracellular AlphaBeta generation, of signaling by the physiological ligand(s) in intact neurons;and 4. to establish the in vivo biochemical and electrophysiological effects of APP signaling in living animals. We will compare the ligand binding and potential signaling properties of APP to those of APLP-1 and APLP-2 and also explore whether APP processing and signaling alter those of Notch. Intriguing preliminary findings about AICD nuclear localization and stabilization by Fe65 and about transcriptional changes in the brains of APP knockout mice encourage us to pursue these aims. The results of the multifaceted experimental approach described herein should be revealing not only for the normal biology of APP but also for how its regulated signaling contributes to the pathogenesis of Alzheimer's disease and to the progressive accumulation of A6 that accompanies normal brain aging in humans and other primates.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG006173-24
Application #
7806585
Study Section
Special Emphasis Panel (NSS)
Program Officer
Refolo, Lorenzo
Project Start
1985-09-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
24
Fiscal Year
2010
Total Cost
$393,520
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Yang, Ting; Li, Shaomin; Xu, Huixin et al. (2017) Large Soluble Oligomers of Amyloid ?-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J Neurosci 37:152-163
Walsh, Dominic M; Selkoe, Dennis J (2016) A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci 17:251-60
Selkoe, Dennis J; Hardy, John (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8:595-608
Jin, Ming; Selkoe, Dennis J (2015) Systematic analysis of time-dependent neural effects of soluble amyloid ? oligomers in culture and in vivo: Prevention by scyllo-inositol. Neurobiol Dis 82:152-163
Holmes, Oliver; Paturi, Swetha; Selkoe, Dennis J et al. (2014) Pen-2 is essential for ?-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry 53:4393-406
Muratore, Christina R; Rice, Heather C; Srikanth, Priya et al. (2014) The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23:3523-36
Morris, John C; Selkoe, Dennis J (2011) Recommendations for the incorporation of biomarkers into Alzheimer clinical trials: an overview. Neurobiol Aging 32 Suppl 1:S1-3
Shepardson, Nina E; Shankar, Ganesh M; Selkoe, Dennis J (2011) Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol 68:1239-44
Jin, Ming; Shepardson, Nina; Yang, Ting et al. (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 108:5819-24
Shepardson, Nina E; Shankar, Ganesh M; Selkoe, Dennis J (2011) Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch Neurol 68:1385-92

Showing the most recent 10 out of 87 publications