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SECRETED BAPP SIGNAL TRANSDUCTION AND NEURAL PLASTICITY
15 April 1997 - 31 January 2001
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Total Funding: $ 666,608
This proposal tests the hypothesis that a secreted form of the beta-amyloid precursor protein (sAPPalpha) plays a role in the development of hippocampal neural circuitry by activating specific receptors linked to a signal transduction pathway that modulates neuronal excitability. The specific aims are (1) To test the hypothesis that sAPPalpha reduces excitability and responses to glutamate by activating a membrane associated guanylate cyclase linked to cGMP production and modulation of K+ channels and NMDA receptors. Studies will be done in cultured hippocampal neurons using whole cell perforated patch clamp analysis of K+ and NMDA induced currents, calcium imaging, analyses of neurotoxicity, assays of cGMP production and a battery of pharmacological tests (2) To define the structure function relationships for activation of the sAPPalpha signaling pathway defined in Aim 1. Recombinant sAPP deletion mutants and synthetic sAPP peptides will be employed (3) To isolate and clone a sAPPalpha receptor, sAPPR. Strategies will include screening already cloned "orphan" receptor guanylate cyclases, isolating and sequencing sAPPalpha-binding proteins, and a yeast interaction trap using LexA fused to sAPPalpha peptides to screen a human fetal brain cDNA fusion library. (4) To map the subcellular localization of the sAPPalpha signal transduction apparatus using immunocytochemical approaches. (5) To test the hypothesis that sAPPalpha regulates neurite outgrowth and synaptogenesis in developing hippocampal neurons via a cGMP-mediated mechanism. Neurite outgrowth and synaptogenesis will be evaluated in embryonic hippocampal cultures using established methods. Collectively these data will reveal the signaling mechanisms of a fascinating multifunctional protein that has been linked to neuronal survival and plasticity, and which may play a role in the deterioration of neuronal circuitry in Alzheimer's disease.
28 Resulting Publications
Peter J Van Ess; Samuel Poloyac; Mark P Mattson; Robert A BlouinPharmaceutical research 2002;19(5):708-12.
Peter J Van Ess; Mark P Mattson; Robert A BlouinThe Journal of pharmacology and experimental therapeutics 2002;300(3):824-30.
P J Van Ess; W A Pedersen; C Culmsee; M P Mattson; R A BlouinJournal of neurochemistry 2002;80(4):571-8.
G W Warren; P J van Ess; A M Watson; M P Mattson; R A BlouinJournal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2001;21(10):821-6.
W A Pedersen; H Luo; I Kruman; E Kasarskis; M P MattsonFASEB journal : official publication of the Federation of American Societies for Experimental Biology 2000;14(7):913-24.
G W Glazner; M P MattsonExperimental neurology 2000;161(2):442-52.
Z H Guo; M P MattsonCerebral cortex (New York, N.Y. : 1991) 2000;10(1):50-7.
G W Glazner; A Boland; A E Dresse; D E Brenneman; I Gozes; M P MattsonJournal of neurochemistry 1999;73(6):2341-7.
W Duan; Z Zhang; D M Gash; M P MattsonAnnals of neurology 1999;46(4):587-97.
D Zhang; H S Dhillon; M P Mattson; D M Yurek; R M PrasadNeuroscience letters 1999;272(1):57-61.
M P MattsonJournal of neuroscience research 1999;57(5):577-89.
S L Chan; S P Tammariello; S Estus; M P MattsonJournal of neurochemistry 1999;73(2):502-12.
W Duan; V M Rangnekar; M P MattsonJournal of neurochemistry 1999;72(6):2312-22.
Q Guo; W Fu; F W Holtsberg; S M Steiner; M P MattsonJournal of neuroscience research 1999;56(5):457-70.
Q Guo; L Sebastian; B L Sopher; M W Miller; G W Glazner; C B Ware; G M Martin; M P MattsonProceedings of the National Academy of Sciences of the United States of America 1999;96(7):4125-30.
G W Warren; S M Poloyac; D S Gary; M P Mattson; R A BlouinThe Journal of pharmacology and experimental therapeutics 1999;288(3):945-50.
Q Guo; L Sebastian; B L Sopher; M W Miller; C B Ware; G M Martin; M P MattsonJournal of neurochemistry 1999;72(3):1019-29.
J G Begley; W Duan; S Chan; K Duff; M P MattsonJournal of neurochemistry 1999;72(3):1030-9.
Z Yu; H Luo; W Fu; M P MattsonExperimental neurology 1999;155(2):302-14.
J N Keller; Q Guo; F W Holtsberg; A J Bruce-Keller; M P MattsonThe Journal of neuroscience : the official journal of the Society for Neuroscience 1998;18(12):4439-50.
Q Guo; N Robinson; M P MattsonThe Journal of biological chemistry 1998;273(20):12341-51.
K Furukawa; M P MattsonJournal of neurochemistry 1998;70(5):1876-86.
Q Guo; S Christakos; N Robinson; M P MattsonProceedings of the National Academy of Sciences of the United States of America 1998;95(6):3227-32.
K Furukawa; M P MattsonNeuroscience 1998;83(2):429-38.
J N Keller; M S Kindy; F W Holtsberg; D K St Clair; H C Yen; A Germeyer; S M Steiner; A J Bruce-Keller; J B Hutchins; M P MattsonThe Journal of neuroscience : the official journal of the Society for Neuroscience 1998;18(2):687-97.
A J Bruce-Keller; J G Begley; W Fu; D A Butterfield; D E Bredesen; J B Hutchins; K Hensley; M P MattsonJournal of neurochemistry 1998;70(1):31-9.
M P MattsonInternational review of neurobiology 1998;42():103-68.
M P Mattson; N Robinson; Q GuoNeuroreport 1997;8(17):3817-21.
This section shows information that has been computed by using the fingerprint of the grant, including related publications, related experts and related grants - all with fingerprints representing significant amounts of overlap between their fingerprint and this grant. The red dots indicate whether those experts or terms actually appear within this grant, showing potential and actual connections.
Cotman, Carl W
30 September 2000 - 31 August 2003
NATIONAL INSTITUTE ON AGING
Total Funding: $ 657,582
TANZI, RUDOLPH E
1 January 1994 - 31 December 1996
NATIONAL INSTITUTE ON AGING
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NATIONAL INSTITUTE ON AGING
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T Wisniewski; J Ghiso; B FrangioneBiochemical and biophysical research communications 1991;179(3):1247-54.
J W Geddes; C W CotmanNeuroscience research 1986;3(6):672-8.
M P MattsonJournal of neurobiology 1994;25(4):439-50.
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