A new mouse model of human tau pathology has been developed, by expression of the normal human tau gene in the absence of mouse tau (hTau mice). These mice show accumulation of phosphorylated tau in the somatodendritic compartment, a clear age-related increase in tau phosphorylation, conformational changes in tau and the formation of filamentous tau aggregates in neocortical, hippocampal and other neurons. There is evidence of astrocytosis, microgliosis and neuronal death in mice aged over a year. Our first goal will be to complete the detailed characterization of the tau pathology that develops in the hTau mice, over the entire life span. These studies will include quantitation of neuronal and synaptic density in neocortex and hippocampus, and examination of astrocytic and microglial reactions. The functional consequences of the development of tau pathology for cholinergic neurotransmission will be examined. The hypothesis that tau isoform ratios are the critical determinant of tau pathology and cell death will be tested by breeding hTau mice with mice expressing single isoforms of human tau as transgenes. In the course of development of hTau mice with different ratios of 3R and 4R tau, mice transgenic for 3R and 4R single isoforms on a null background will be generated, and these mice will be examined for the development of tau pathology. The possible role of a new gene, saitohin, discovered to reside within an intron of the human tau gene, will be examined by single and double label immunocytochemistry, and by biochemical techniques. The hypothetical roles of GSK3beta, cdk5 and other protein kinases in the formation of hyperphosphorylated tau aggregates will be examined using biochemical, pharmacological and genetic strategies. Finally, if neuronal death is confirmed to occur in the hTau mice, potential mechanisms will be explored, with special attention paid to the possibility that apoptosis is involved. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG022102-04
Application #
7028879
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Miller, Marilyn
Project Start
2003-05-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$395,458
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Vitale, Francesca; Giliberto, Luca; Ruiz, Santiago et al. (2018) Anti-tau conformational scFv MC1 antibody efficiently reduces pathological tau species in adult JNPL3 mice. Acta Neuropathol Commun 6:82
d'Abramo, Cristina; Acker, Christopher M; Schachter, Joel B et al. (2016) Detecting tau in serum of transgenic animal models after tau immunotherapy treatment. Neurobiol Aging 37:58-65
d'Abramo, Cristina; Acker, Christopher M; Jimenez, Heidy et al. (2015) Passive Immunization in JNPL3 Transgenic Mice Using an Array of Phospho-Tau Specific Antibodies. PLoS One 10:e0135774
Rubenstein, Richard; Chang, Binggong; Petersen, Robert et al. (2015) T-Tau and P-Tau in Brain and Blood from Natural and Experimental Prion Diseases. PLoS One 10:e0143103
Acker, Christopher M; Forest, Stefanie K; Zinkowski, Ray et al. (2013) Sensitive quantitative assays for tau and phospho-tau in transgenic mouse models. Neurobiol Aging 34:338-50
Koppel, Jeremy; Sunday, Suzanne; Buthorn, Justin et al. (2013) Elevated CSF Tau is associated with psychosis in Alzheimer's disease. Am J Psychiatry 170:1212-3
Forest, Stefanie K; Acker, Christopher M; d'Abramo, Cristina et al. (2013) Methods for measuring tau pathology in transgenic mouse models. J Alzheimers Dis 33:463-71
d'Abramo, Cristina; Acker, Christopher M; Jimenez, Heidy T et al. (2013) Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS One 8:e62402
Dreses-Werringloer, Ute; Vingtdeux, Valérie; Zhao, Haitian et al. (2013) CALHM1 controls the Ca²?-dependent MEK, ERK, RSK and MSK signaling cascade in neurons. J Cell Sci 126:1199-206
Chapuis, Julien; Vingtdeux, Valérie; Capiralla, Hemachander et al. (2012) Gas1 interferes with A?PP trafficking by facilitating the accumulation of immature A?PP in endoplasmic reticulum-associated raft subdomains. J Alzheimers Dis 28:127-35

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