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Craig S. AtwoodPh.D., University of Western Australia, Perth |
Hormonal Regulation of Aging and Neurodegenerative Diseases
Research in my laboratory draws together my interests and expertise in reproductive endocrinology and neuroscience in order to examine experimentally the hormonal regulation of aging and Alzheimer’s disease. The basic premise behind the research is that hormones that regulate reproduction in mammals act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence.
There are two major research themes in the laboratory. The first is to examine the role of the hypothalamic-pituitary gonadal axis in neurodegeneration associated with Alzheimer’s disease (i.e. in synaptic and neuronal loss, amyloid deposition and neurofibrillary tangle formation). Current research projects in this area include investigation of the hormonal regulation of neuronal: 1). gene/protein expression with aging and in particular following menopause/andropause, 2). APP processing and amyloid deposition, 3). cell proliferation and re-entry of differentiated neurons into the cell cycle, 4). oxidative stress and 5). metal ion homeostases. The second research theme examines the modulation of healthy aging and lifespan. Current research projects include understanding the role of pituitary hormones in modulating healthy aging and lifespan, with an emphasis on utilizing pituitary hormone lowering drugs to dissect hormonal pathways that promote longevity and their mechanism of action.
A number of different animal (from C. elegans to humans) and in vitro (cell lines and primary cells) models are used to address how the dysregulation of the hypothalamic-pituitary-gonadal axis during menopause/andropause drives both aging and age-related diseases, particularly Alzheimer's disease. Dr. Atwood's laboratory utilizes a variety of techniques including molecular biology (microarray technologies), histology, and protein (proteomics), lipid and oxidative chemistries in order to gain insights into these aging processes. Recent experimental work has been instrumental in showing that leuprolide acetate, currently used for the treatment of prostate cancer, may be effective in reversing Alzheimer's disease pathology. Leuprolide acetate is now in Phase II clinical trials for the treatment of this disease.
Representative Publications
Atwood, C.S., Perry, G., Zeng, H., Kato, Y., Jones, W.D., Huang, X., Chen, S., Sayre, L.M., Ling, K.-Q., Smith M.A., & Bush, A.I. (In Press)Copper mediated crosslinking reactions of Alzheimer's amyloid-β. Biochemistry.
Xu, G., McLaren, D.G., Ries, M.L., Fitzgerald, M.E., Bendlin, B.B., Rowley, H.A., Sager, M.A., Atwood, C.S., Asthana, S., & Johnson, S.C. (2009). The influence of parental history of Alzheimer's disease and apolipoprotein E 4 on the BOLD signal during recognition memory. Brain, 132, 383-391.
Atwood, C.S., & Bowen, R.L. (2008). A multi-hit endocrine model of intrinsic adult-onset asthma. Ageing Research Reviews, 7(2), 114-125.
Chan, H.W., Liu, T., Verdile, G., Bishop, G.M., Haasl, R.J., Smith, M.A., Perry, G., Martins, R.N., & Atwood, C.S. (2008). Copper induces apoptosis of neuroblastoma cells via post-translational regulation of the expression of Bcl-2-family proteins and the txJ mouse is a better model of hepatic than brain Cu toxicity. International Journal of Clinical and Experimental Medicine, 1, 76-86.
Gonzalez-Cuyar, L.F., Perry, G., Miyajima, H., Atwood, C.S., Riveros-Angel, M., Lyons, P.F., Siedlak, S.L., Smith, M.A., & Castellani, R.J. (2008). Redox active iron accumulation in aceruloplasminemia. Neuropathology. [Epub ahead of print].
Haasl, R.J., Reza Ahmadi, M., Vadakkadath Meethal, S., Gleason, C.E., Johnson, S.C., Asthana, S., Bowen, R.L., & Atwood, C.S. (2008). A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer’s disease in males carrying an apolipoprotein E e4 Allele. BMC Medical Genetics, 9(1), 37.
Rodrigues, M.A., Verdile, G., Foster, J.K., Hogervorst, E., Joesbury, K., Dhaliwal, S., Corder, E.H., Laws, S.M., Hone, E., Prince, R., Devine, A., Mehta, P., Beilby, J., Atwood, C.S., & Martins, R.N. (2008). Gonadotropins and cognition in older women. Journal of Alzheimer’s Disease, 13(3), 267-274.
Wilson, A.C., Clemente, L., Liu, T., Bowen, R.L., Vadakkadath Meethal, S., & Atwood, C.S. (2008). Reproductive hormones regulate the selective permeability of the blood-brain barrier. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1782(6), 401-7.
Friedland, R.P., Tedesco, J., Wilson, A.C., Atwood, C.S., Smith, M.A., Perry, G., Zagorski, M.G. (2008). Antibodies to potato virus Y bind the A-beta protein: Immunohistochemical and NMR studies. Journal of Biological Chemistry, 283(33), 22550-22556.
Gallego, M.J., Porayette, P., Kaltcheva, M.M., Vadakkadath Meethal, S., & Atwood, C.S. (2008). Opioid and progesterone signaling is obligatory for early human embryogenesis. Stem Cells and Development. [Epub ahead of print].
Carlsson, C.M., Gleason, C.E., Hess, T.M., Moreland, K.A., Blazel, H.M., Koscik, R.L., Schreiber, N.T.N., Johnson, S.C., Atwood, C.S., Puglielli, L., Hermann, B.P., McBride, P.E., Stein, J.H., Sager, M.A., & Asthana, S. (2008). Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimers disease. Journal of Alzheimers Disease, 13(2), 187-97.
Trivedi, M.A., Schmitz, T.W., Ries, M.L., Hess, T.M., Fitzgerald, M.E., Atwood, C.S., Rowley, H.A., Asthana, S., Sager, M.A., & Johnson, S.C. (2008). fMRI activation during episodic encoding and metacognitive appraisal across the lifespan: Risk factors for Alzheimer's disease. Neuropsychologia, 46(6), 1667-1678.
Bishop, G.M., Smith, M.A., LaManna, J.C., Wilson, A.C., Perry, G., & Atwood, C.S. (2007). Iron homeostasis is maintained in the brain, but not the liver, following mild hypoxia. Redox Report, 12(6), 257-266.
Liu, T., Wimalasena, J., Bowen, R.L., & Atwood, C.S. (2007). Luteinizing hormone receptor mediates neuronal pregnenolone production via upregulation of steroidogenic acute regulatory protein expression. Journal of Neurochemistry, 100(5), 1329-1339.
Porayette, P., Gallego, M.J., Kaltcheva, M.M., Vadakkadath Meethal, S., & Atwood, C.S. (2007). Amyloid-b precursor protein expression and modulation in human embryonic stem cells: A novel role for human chorionic gonadotropin. Biochemical and Biophysical Research Communications, 364(3), 522-527.
Wung, J.K., Perry, G., Kowalski, A.., Harris, P.L.R., Bishop, G.M., Trivedi, M.A., Johnson, S.C., Smith, M.A., Denhardt, D.T., & Atwood, C.S. (2007). Increased expression of the remodeling- and tumorigenic-associated factor osteopontin in pyramidal neurons of the alzheimer's disease brain. Current Alzheimer Research, 4(1), 67-72.
Gleason, C.E., Carlsson, C.M., Johnson, S.C., Atwood, C., & Asthana, S. (2005). Clinical pharmacology and differential cognitive efficacy of estrogen preparations. Annals of the New York Academy of Science, 1052, 93-115.
Liu, T., Perry, G., Chan, H.W., Verdile, G., Martins, R.N., Smith, M.A., & Atwood, C.S. (2004). Amyloid-β-induced toxicity of primary neurons is dependent upon differentiation associated increases in tau and cyclin-dependent kinase 5. Journal of Neurochemistry, 88(3), 554-563.
Bowen, R.L., Verdile, G., Liu, T., Parlow, A.F., Perry, G., Smith, M.A., Martins, R.N., & Atwood, C.S. (2004). Luteinizing Hormone, a Reproductive Regulator that Modulates the Processing of Amyloid-beta Precursor Protein and Amyloid-beta Deposition. J. Biol. Chem, 279, 20539 - 20545.
Veurink, G., Liu, D., Taddei, K., Perry, G., Smith, M.A., Robertson, T.A., Hone, E., Groth, D.M., Atwood, C.S., & Martins, R.N. (2003). Reduction of inclusion body pathology in Apo-E-deficient mice fed a combination of antioxidants. Free Radicals in Biology and Medicine, 34(8), 1070-1077.
Dong, J., Atwood, C.S., Anderson, V.E., Siedlak, S.L., Smith, M.A., Perry, G., & Carey, P.R. (2003). Metal binding and oxidation of amyloid-β within isolated senile plaque cores: Raman microscopic evidence. Biochemistry, 42(10), 2768-2773.
Atwood, C.S., Barzilai, N., Bowen, R.L., Brown-Borg, H.M., Jarrard, D.F., Fu, V.X., Heilbronn, L.K., Ingram, D.K., Ravussin, E., Schwartz, R.S., & Weindruch, R. (2003). Pennington scientific symposium on mechanisms and retardation of aging. Experimental Gerontology, 38(10), 1217-1226.
Bowen, R.L., Smith, M.A., Harris, P.L.R., Kubat, Z., Martins R.N., Castellani, R.J., Perry, G., & Atwood, C.S. (2002). Elevated luteinizing hormone expression colocalizes with neurofibrillary tangles in Alzheimer disease. Journal of Neuroscience Research, 70(3), 514-518.
Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A. Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y.-S., Huang, X., Goldstein, L.E., Moir, R.D., Lim, J.T., Beyreuther, K.T., Zheng, H., Tanzi, R.E., Masters, C.L., & Bush, A. (2001). Treatment of a copper-zinc chelator markedly and rapidly inhibits β-Amyloid accumulation in Alzheimer disease transgenic mice. Neuron, 30, 665-676.
Atwood, C.S., Hovey, R., Glover, J.P., Chepko, G., Ginsburg, E., Robison, Jr., W.G., & Vonderhaar, B.K. (2000). Progesterone induces ductal side-branching of the ductal epithelium in the mammary glands of peripubertal mice. Journal of Endocrinology, 167, 39-52.
Atwood, C.S., Scarpa, R.C., Huang, X., Moir, R.D., Jones, W.D., Fairlie, D.P., Tanzi, R.E., & Bush, A.I. (2000). Characterization of copper interactions with Alzheimer amyloid beta peptides: Identification of an attomolar-affinity copper binding site on amyloid beta1-42. Journal of Neurochemistry, 75, 1219-1233.
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