Neurofibrillary inclusions composed of the microtubule associated protein tau (tau) are a hallmark feature ot the pathology in several neurodegenerative diseases including Alzheimer's disease, Progressive supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). A causal link between tau dysfunction and neurodegeneration was demonstrated by the idenification of mutations in tau that give rise to FTDP-17. The overall goal of this current program is to identify modifiers that influence the progression of tau pathology, in human neurodegenerative disease and to build on this information to identify therapeutic targets that will form the basis for eventual patient treatments. This goal follows on naturally from the progress made in the first period of funding in which this Program was highly successful in developing both cell culture and transgenic animal models of tauopathy as well as in characterizing the genetic causes of these diseases. The four projects, alongwith a central Neuropathology core, that make up this program will address this overall goal through different but complementary strategies. Project 1 (Dr Farrer) will utilize a genetic approach to identify tau gene variants that increase the risk for developing 4R tauopathy (PSP and CBD) and will determine the mechanism by which these variants lead to disease. This project will thus define a potential therapeutic target in these diseases. Project 2 (Dr Yen) will utilize a cell culture model of early stage tau filament formation and pathogenesis to study the impact of several factors that have been suggested as causes of tauopathy (eg oxidative stress, proteasome inhibition). This project will identify modifiers of tau pathogenesis in this cell model that can then be studied in our transgenic models. Projects 3 (Hutton) and 4 (Duff) will employ transgenic mouse models of tauopathy developed by the Program over the past 4 years to study potential targets already identified by preliminary studies. Project 3 will study the impact of the chaperone Hsp70 and its co-chaperone CHIP on tau pathogenesis whilst Project 4, will examine the impact of tau phosphorylation on pathology and neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017216-09
Application #
7434416
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (O2))
Program Officer
Miller, Marilyn
Project Start
1999-09-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
9
Fiscal Year
2008
Total Cost
$1,318,457
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Kidana, Kiwami; Tatebe, Takuya; Ito, Kaori et al. (2018) Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice. EMBO Mol Med 10:
Li, Zeran; Del-Aguila, Jorge L; Dube, Umber et al. (2018) Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure. Genome Med 10:43
Sun, Wenyan; Samimi, Hanie; Gamez, Maria et al. (2018) Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21:1038-1048
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Carrasquillo, Minerva M; Allen, Mariet; Burgess, Jeremy D et al. (2017) A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimers Dement 13:663-673
Miller, Jeremy A; Guillozet-Bongaarts, Angela; Gibbons, Laura E et al. (2017) Neuropathological and transcriptomic characteristics of the aged brain. Elife 6:
Sanchez-Contreras, Monica; Heckman, Michael G; Tacik, Pawel et al. (2017) Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration. Mov Disord 32:115-123
Carrasquillo, Minerva M; Barber, Imelda; Lincoln, Sarah J et al. (2016) Evaluating pathogenic dementia variants in posterior cortical atrophy. Neurobiol Aging 37:38-44
Allen, Mariet; Carrasquillo, Minerva M; Funk, Cory et al. (2016) Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases. Sci Data 3:160089
Caberlotto, Laura; Marchetti, Luca; Lauria, Mario et al. (2016) Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer's disease. Sci Rep 6:32583

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