Characterizing effects of reducing tau expression in adulthood

Erik Roberson, MD, PhD
University of Alabama at Birmingham (Birmingham, AL)
Year Awarded:
2010
Grant Duration:
April 1, 2010 to March 31, 2013
Disease:
Alzheimer's
Award Amount:
$150,000
Grant Reference ID:
A2010364
Award Type:
Pilot
Award Region:
US Southeastern
This grant is made possible due to a generous bequest from the Trust of W. Dean Cannon, Jr.

Characterizing protective effects of induced tau reduction

Summary

Tau may serve as an excellent treatment target in Alzheimer's disease Alzheimer's disease, and we recently found that genetic elimination of tau had a strong protective effect in mouse models of Alzheimer's disease. In those studies, tau was absent in the animals starting at conception, and throughout their lives. The proposed research will address the critical question of whether reducing tau expression in adulthood, which is more relevant therapeutically, has similar protective effects.

Details

Alzheimer's disease Alzheimer's disease researchers are searching intently for new strategies to treat this disease, with much effort devoted to reducing levels of the "amyloid beta" peptide that is believed to cause the disease. We recently identified a strategy in mouse models of Alzheimer's disease to make the brain resistant to amyloid beta, by genetically eliminating a protein called tau. We believe that tau reduction, or finding drugs that accomplish the same downstream effects, could be a useful strategy for treating Alzheimer's disease. In the mice that we have studied, however, tau was absent throughout life, so we don't know yet if tapping into this strategy in adults would be safe or effective. The goal of this project is to characterize a second-generation line of mice that we are developing, in which tau reduction can be triggered at any stage of life by administering a specific drug. Our goal in the present study is to induce tau reduction in adult mice, and to determine if this can be accomplished without adverse effects and with the beneficial effects that we see when tau is absent from conception. After inducing tau reduction in adult mice, we will perform tests of general health, learning and memory, motor coordination, and other brain functions, and will also examine brain architecture under the microscope, to ensure that no major side effects have occurred. Then, we will determine if the brains of these mice are resistant to the kinds of abnormal brain activity that we observe in Alzheimer's disease mouse models, as we know mice lacking tau from birth are. These studies will address one of the major issues on the way to translating our success in preventing deficits in mouse models into a tractable strategy for patients with or at risk for Alzheimer's disease.

Research Updates

Dr. Roberson’s team previously found that genetic elimination of tau had a strong protective effect in mouse models of AD, suggesting that tau may serve as an excellent treatment target in Alzheimer’s disease (AD). In those studies, tau was absent in the mice starting at conception and throughout their lives. In the proposed experiments, the team is addressing the critical question of whether reducing tau expression in adulthood, which is more relevant therapeutically, has similar protective effects. Therefore, they generated a new mouse model where tau is only reduced once the mice become adults. Dr. Roberson’s team has validated this system, has successfully induced tau reduction in adulthood, and is currently testing its effects. Should these mice also be protected from Alzheimer’s, then this would support the idea that a future treatment to reduce levels of tau or to reproduce the effects of tau reduction could have a protective effect against the disease.

Publications

Roberson, E.D. (2011) Contemporary approaches to Alzheimer's disease and frontotemporal dementia. Methods Mol. Biol. 670, 1-9 PubMed Icon Google Scholar Icon


Roberson, E.D., et al. (2011) Amyloid-?/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J. Neurosci. 31, 700-711 PubMed Icon Google Scholar Icon

Palop, J.J., Roberson, E.D., and Cobos, I. (2011) Step-by-step in situ hybridization method for localizing gene expression changes in the brain. Methods Mol Biol 670, 207-230  PubMed Icon Google Scholar Icon

Palop, J.J., Mucke, L., and Roberson, E.D. (2011) Quantifying biomarkers of cognitive dysfunction and neuronal network hyperexcitability in mouse models of Alzheimer's disease: depletion of calcium-dependent proteins and inhibitory hippocampal remodeling. Methods Mol. Biol. 670, 245-262 PubMed Icon Google Scholar Icon

Jun, G., Naj, A.C., Beecham, G.W., Wang, L.S., Buros, J., Gallins, P.J., Buxbaum, J.D., Ertekin-Taner, N., Fallin, M.D., Friedland, R., Inzelberg, R., Kramer, P., Rogaeva, E., St George-Hyslop, P., Alzheimer's Disease Genetics Consortium (including Roberson E.D. and others), Cantwell, L.B., Dombroski, B.A., Saykin, A.J., Reiman, E.M., Bennett, D.A., Morris, J.C., Lunetta, K.L., Martin, E.R., Montine, T.J., Goate, A.M., Blacker, D., Tsuang, D.W., Beekly, D., Cupples, L.A., Hakonarson, H., Kukull, W., Foroud, T.M., Haines, J., Mayeux, R., Farrer, L.A., Pericak-Vance, M.A., and Schellenberg, G.D. (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch. Neurol. 67, 1473-1484 PubMed Icon Google Scholar Icon



Roberson, E.D., O.A. Hope, R.C. Martin, and D. Schmidt. (2011). Geriatric epilepsy: Research and clinical directions for the future. PubMed Icon Google Scholar Icon

Hall, A.M. and E.D. Roberson.† (2012). Mouse models of Alzheimer’s disease. Br. Res. Bull. 88:3–12. PubMed Icon Google Scholar Icon