Room 203, Sanders-Brown Center On Aging
800 South Limestone Street
Lexington, KY 40536-0230
Molecular and Biomedical Pharmacology andSanders-Brown Center on Aging
Prevention and Treatment of Alzheimer’s Disease
Left to right: Amy Dowling, Susan Martin, Susan Wang, Heather Murphey, Jonathan Nitz, Katie McCarty, Samuel Bethel, Joseph Kercsmar
The goals of our research are to identify interventions that may prevent the onset and/or progression of Alzheimer’s disease and thus promote healthy brain aging. To do this, our lab tests hypotheses using a canine model of human brain aging. Our focus is on testing combinations of treatments, each targeting different pathological pathways associated with aging or Alzheimer’s disease. Aging canines naturally develop learning and memory impairments, as well as similar types of brain pathology as humans. Our studies are multidisciplinary and range from magnetic resonance imaging (MRI) to testing cognitive function (learning and memory) and neurobiological studies (anatomical, genomics and proteomics). We currently have two canine studies in progress: (1) to identify gene expression changes in the brains of aged animals treated either with a diet high in antioxidants/mitochondrial co-factors, or with behavioral enrichment or treated with a combination of both diet and enrichment; (2) to test the hypothesis that vaccination with beta-amyloid peptide when combined with behavioral enrichment will lead to significant improvements in cognition and reductions in neuropathology in aged canines.
In parallel with work in animal model systems, our laboratory is also following learning and memory changes with aging in adults with Down syndrome http://www.uky.edu/DSAging/). People with Down syndrome are at a high risk for developing Alzheimer’s disease because they have an extra copy of chromosome 21 and the overexpress beta-amyloid protein. Our study participants undergo neuropsychological tests, a neurological and physical examination and magnetic resonance imaging. In addition, blood samples are drawn and a variety of protein levels are being measured. In the future, we hope that treatments developed in the canine model can be translated to people with Down syndrome to slow or prevent the development of Alzheimer’s disease.
Head, E., H. Callahan, B.A. Muggenberg, and C.W. Cotman and Milgram, N.W. (1998) Visual Discrimination Learning Ability and Beta-amyloid Accumulation in the Dog. Neurobiology of Aging, 19: 415-425.
Head, E., McCleary, R., Hahn, F.F, Milgram, N.W. and Cotman, C.W. (2000) Region-specific age at onset of b-amyloid in dogs. Neurobiology of Aging, 21(1): 89-96.
Head, E., Liu, J., Hagen, T.M., Muggenburg, B.A., Milgram, N.W., Ames, B.N., and Cotman, C.W. (2002) Oxidative damage increases with age in a canine model of human brain aging. Journal of Neurochemistry, 82: 375-381.
Milgram, N.W.,Head, E., Zicker, SC., Ikeda-Douglas, C.J., Murphey, H. Muggenburg, B. Siwak, C., Tapp, D, Cotman, CW (2005). Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: A two-year longitudinal study. Neurobiology of Aging. 26:77-90.
Tapp, D.T., Head, K.,Head, E., Milgram, N.W., Muggenburg, B.A., Su, M.-Y. 2006). Application of an Automated Voxel-based Morphometry Technique to Assess Regional Gray and White Matter Brain Atrophy in a Canine Model of Aging. NeuroImage, 29(1): 234-244.
E. Head,E.G. Barrett, M. P. Murphy, P. Das, M. Nistor, F. Sarsoza, C. Glabe, R. Kayed, S. Milton, V. Vasilevko, N. W. Milgram, M. G. Agadjanyan, D. H. Cribbs, C. W. Cotman (2006).Immunization with fibrillar Ab1-42in young and aged canines: Antibody Generation and Characteristics, and effects on CSF and Brain Ab. Vaccine, 24: 2824-2834.
Milgram, N.W., Siwak-Tapp, C.T., Araujo, J.,Head, E.(2006). Neuroprotective effects of cognitive enrichment. Ageing Research Reviews, 5: 354-369.
Siwak-Tapp, C.T.,Head, E., Muggenburg, B.A., Milgram, N.W., and Cotman, C.W. (2007) Neurogenesis Decreases with Age in the Canine Hippocampus and Correlates with Cognitive Function. Neurobiology of Learning and Memory, 88(2): 249-259.
Opii,W.O., Joshi , G.,Head, E., Milgram, N.W., Muggenburg, B.A., Klein, J.B., Pierce, W.M., Cotman, C.W., Butterfield, D.A.. (2008). Proteomic Identification of Brain Proteins in the Canine Model of Human Aging Following a Long-Term Treatment with Antioxidants and a Program of Behavioral Enrichment: Relevance to Alzheimer’s Disease. Neurobiology of Aging, 29(1): 51-70.
Head, E., V. Pop, V. Vasilevko, M. Hill , T. Saing, F. Sarsoza, M. Nistor, L.A. Christie, S. Milton, C. Glabe, E. Barrett, and D. Cribbs (2008). A 2-Year Study with Fibrillar Ab Immunization in Aged Canines: Effects on Cognitive Function and Brain Ab. Journal of Neuroscience, 28: 3555-3566.
Head, E. (2008). Oxidative Damage and Cognitive Dysfunction: Antioxidant Treatments to Promote Healthy Brain Aging. Neurochemical Research, August 6: Epub.
Cotman, CW,Head, E.(2008). The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J. Alzheimers Dis. 15(4): 685-707.
Cotman, C.W. andE. Head(2008). The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J. Alzheimers Dis. 15(4): 685-707.
Sarsoza, F., T. Saing, R. Kayed, R. Dahlin, M. Dick, C. Broadwater-Hollifield, S. Mobley, I. Lott, E. Doran, D. Gillen, C. Anderson-Bergman, D.H. Cribbs, C. Glabe, andE. Head(2009). A fibril specific, conformation dependent antibody recognizes a subset of Aβ plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain. Acta Neuropathologica. 118 (4) 505.
Head, E., V.N. Nukala, K.A. Fenoglio, B.A. Muggenburg, C.W. Cotman and P.G. Sullivan, (2009). Effects of age, dietary and behavioral enrichment on brain mitochondria in a canine model of human aging. Experimental Neurology, 220(1): 171-176.
Vasilevko, V. andE. Head(2009). Immunotherapy in a natural model of Abeta pathogenesis: The aging beagle. CNS Neurol Disord Drug Targets, 8: 98-113.
Head, E., V. Pop, F. Sarsoza, R. Kayed, T.L. Beckett, C.M. Studzinski, J.L. Tomic, C.G. Glabe, and M.P. Murphy (2010). Amyloid beta-peptide and oligomers in the brain and CSF of aged canines. Journal of Alzheimer’s Disease, 20(2): 637-646.
Vasilevko, V., V. Pop, H.J. Kim, T. Saing, C.G.Glabe, S. Milton, E.G. Barrett, C.W. Cotman, D.H. Cribbs,andE.Head(2010).Linear and conformation specific antibodies in aged beagles after prolonged vaccination with aggregated Aβ.Neurobiology of Disease, 39(3): 301-310.
Pop, V.,E. Head, M.A. Hill, D. Gillen, N.C. Berchtold, B.A. Muggenburg, N.W. Milgram, M.P. Murphy, and C.W. Cotman (2010). Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines. Journal of Neuroscience, 30(29):9831-9839.
Head, E., E. Doran, M. Nistor, M., F.A. Schmitt, R.J. Haier, and I.T. Lott (2010). Plasma Aβ as a function of age, level of intellectual disability and presence of dementia in Down syndrome. Journal of Alzheimer’s disease, in press.