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Aging and Dementia: Cholinergic neuron biochemistry
1 March 2006 - 28 February 2011
NATIONAL INSTITUTE OF MENTAL HEALTH
Total Funding: $ 4,531,594
This work is designed to build on our growing understanding of the mechanism by which tau becomes abnormal in Alzheimer's disease, and the critical factors that lead to tangle formation and cell death. We now seek to test new specific hypotheses regarding the mechanisms responsible for these events. Tyrosine phosphorylation of tau seems to be a very early event in AD, and the kinases responsible for these phosphorylations will be a major focus of this application. Mechanisms that can activate these kinases will also be examined to determine if associations with pathology can be demonstrated. New data on an apparent AD-specific phosphorylation of APP and the binding of Pin1 have suggested approaches to examination of the relationship between changes in APP processing and tau pathology. The specific aims are: 1. We will test the hypothesis that phosphorylation of tau on Y18 and/or 394 are candidates for production of conformational changes in tau in AD. Fyn and abl are the kinases that may be responsible for these phosphorylations, and the association of these proteins with tau pathology will be examined in detail. 2. The hypothesis that Abeta deposition triggers activation of src family kinases (and tyrosine phosphorylation of tau) has been proposed by others, and this will be tested in a rigorous fashion in the AD brain. The accumulation of pY18, fyn and abl with Abeta will be examined by immunocytochemistry using the same tissues employed in Aim 1. The possibility that Abeta effects on tyrosine phosphorylation of tau might be indirectly mediated through microglial production of TNF alpha will also be examined. 3. The interaction of tau with fyn and abl will be further examined in cultured cells. Cells will be transfected with specific tau isoforms along with fyn or abl. The hypothesis that tyrosine phosphorylation of tau causes conformational changes that may be sensitive to tau isoform composition will be tested. 4. We will test the hypothesis that changes in APP processing can induce changes in tau conformation and phosphorylation in cell culture systems selected to have a variety of tau isoform compositions. 5. Pin1 binds to both phosphorylated tau and phosphorylated APP, and both sites are phosphorylated in the AD brain. The hypothesis that Pin1 is involved in conformation changes of tau and perhaps in modifying APP processing will be tested. This work will help understand the process of AD, and help lead to new therapeutic strategies.
33 Resulting Publications
Jason G Weinger; Peter Davies; Christopher M Acker; Celia F Brosnan; Vladislav Tsiperson; Ashrei Bayewitz; Bridget Shafit-ZagardoJournal of neuropathology and experimental neurology 2012;71(5):422-33.
C Conejero-Goldberg; T M Hyde; S Chen; U Dreses-Werringloer; M M Herman; J E Kleinman; P Davies; T E GoldbergMolecular psychiatry 2011;16(8):836-47.
Allal Boutajangout; Johanna Ingadottir; Peter Davies; Einar M SigurdssonJournal of neurochemistry 2011;118(4):658-67.
Parastoo Momeni; Karen DeTucci; Richard E Straub; Daniel R Weinberger; Peter Davies; Jordan Grafman; John Hardy; Edward D HueyNeurocase 2010;16(3):273-9.
Leonel E Rojo; Jans Alzate-Morales; Iván N Saavedra; Peter Davies; Ricardo B MaccioniJournal of Alzheimer's disease : JAD 2010;19(2):573-89.
Matthew A Tremblay; Christopher M Acker; Peter DaviesJournal of Alzheimer's disease : JAD 2010;19(2):721-33.
Shuxin Hu; Aynun N Begum; Mychica R Jones; Mike S Oh; Walter K Beech; Beverly Hudspeth Beech; Fusheng Yang; Pingping Chen; Oliver J Ubeda; Peter C Kim; et al.Neurobiology of disease 2009;33(2):193-206.
Peter Davies; Jeremy KoppelDialogues in clinical neuroscience 2009;11(2):159-69.
Concepcion Conejero-Goldberg; Kirk Townsend; Peter DaviesJournal of molecular neuroscience : MN 2008;35(2):143-50.
Marisol Espinoza; Rohan de Silva; Dennis W Dickson; Peter DaviesJournal of Alzheimer's disease : JAD 2008;14(1):1-16.
Howard A Crystal; Peter DaviesNeurology 2008;70(8):586-7.
Concepcion Conejero-Goldberg; Peter Davies; Luis UlloaNeuroscience and biobehavioral reviews 2008;32(4):693-706.
A Z Herskovits; P DaviesNeurobiology of disease 2006;23(2):398-408.
Philippe Marambaud; Haitian Zhao; Peter DaviesThe Journal of biological chemistry 2005;280(45):37377-82.
Pankajavalli Ramakrishnan; Dennis W Dickson; Peter DaviesNeurobiology of disease 2003;14(2):251-64.
Cathy Andorfer; Yvonne Kress; Marisol Espinoza; Rohan de Silva; Kerry L Tucker; Yves-Alain Barde; Karen Duff; Peter DaviesJournal of neurochemistry 2003;86(3):582-90.
Bitao Bu; Jin Li; Peter Davies; Inez VincentThe Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22(15):6515-25.
S P Zamora-Leon; G Lee; P Davies; B Shafit-ZagardoThe Journal of biological chemistry 2001;276(43):39950-8.
C A Andorfer; P DaviesDevelopmental neuroscience 2000;22(4):303-9.
B H Anderton; L Callahan; P Coleman; P Davies; D Flood; G A Jicha; T Ohm; C WeaverProgress in neurobiology 1998;55(6):595-609.
I A Simpson; K R Chundu; T Davies-Hill; W G Honer; P DaviesAnnals of neurology 1994;35(5):546-51.
I Vincent; M Rosado; E Kim; P DaviesJournal of neurochemistry 1994;62(2):715-23.
I J Vincent; P DaviesProceedings of the National Academy of Sciences of the United States of America 1992;89(7):2878-82.
I J Vincent; P DaviesBrain research 1990;531(1-2):127-35.
S G Greenberg; P DaviesProceedings of the National Academy of Sciences of the United States of America 1990;87(15):5827-31.
B Wolozin; A Scicutella; P DaviesProceedings of the National Academy of Sciences of the United States of America 1988;85(16):6202-6.
A Scicutella; P DaviesJournal of neuropathology and experimental neurology 1988;47(4):406-19.
H Ksiezak-Reding; P Davies; S H YenThe Journal of biological chemistry 1988;263(17):7943-7.
B R Zisman; V Braunstein; Y Kress; P DaviesNeurobiology of aging 1988;9(2):207-12.
J A Doebler; W R Markesbery; A Anthony; P Davies; S W Scheff; R E RhoadsAnnals of neurology 1988;23(1):20-4.
D Casper; P DaviesDevelopmental neuroscience 1988;10(4):245-55.
L J Thal; P DaviesJournal of the American Geriatrics Society 1987;35(12):1047-50.
P DaviesAnnals of the New York Academy of Sciences 1985;444():212-7.
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SCHMECHEL, DONALD E
1 May 1988 - 30 April 1993
NATIONAL INSTITUTE ON AGING
Total Funding: $ 588,660
Cole, Gregory M
1 September 2005 - 31 August 2009
NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
Total Funding: $ 1,072,290
Cole, Gregory M
30 September 2001 - 31 August 2007
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Total Funding: $ 1,285,000
Sang-Ho Choi; Saba Aid; Luca Caracciolo; S Sakura Minami; Takako Niikura; Yasuji Matsuoka; R Scott Turner; Mark P Mattson; Francesca BosettiJournal of neurochemistry 2013;124(1):59-68.
J Tan; T Town; D Paris; T Mori; Z Suo; F Crawford; M P Mattson; R A Flavell; M MullanScience (New York, N.Y.) 1999;286(5448):2352-5.
P J Whitehouse; J R UnnerstallEuropean neurology 1988;28 Suppl 1():36-41.
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