UK
Department of Anatomy and Neurobiology Faculty
Research
ANNADORA J.
BRUCE-KELLER, Ph.D.
University of Southern California (1995)
Postdoctoral training at University of Kentucky
Associate Professor of Anatomy and Neurobiology
Research Interests:
Hormones, Immunology and the Brain
Why are women more
likely then men to develop Alzheimer’s disease in later life? Why do more
women then men suffer from autoimmune disorders?
The answers to
these questions lie buried in complex interactions between the endocrine system,
immune system, and the nervous system. In the broadest sense, our lab is studying
these interactions, with specific emphasis on the effects of estrogen on immune
and neuro-immune function. For instance, we have determined that physiological
doses of estrogen can decrease microglial activation. This observation may have
important ramifications for age-related neuro-immune disorders, such as Alzheimer’s
disease. As the principle brain-resident immunocompetent cell, microglial cells
have an elaborate repertoire
of cellular responses to defend the brain from external threats, including the
ability to secrete low-molecular weight neurotoxins, free radicals, and complement
factors; as well as the ability to phagocytize foreign bodies and damaged tissue.
However, based on the extreme cytotoxic potential of these neuro-inflammatory
pathways, it can proposed that prolonged microglial activation in the brain
contributes to (if not carries) brain injury, and should be pharmacologically
abated. Hence, plummeting estrogen levels in post-menopausal women may be a
factor in the development of AD by allowing for unchecked microglial activation.
This association between estrogen and microglial activation may partially explain
why both estrogen replacement therapy and long-term anti-inflammatory drug therapy
decreases a women’s risk for AD.
Additionally,
estrogen has extremely potent effects on the immune system, as evidencedby both
the increased prevalence of autoimmune disorders in women and in the alterations
in humoral immunity during pregnancy. We have recently become very interested
in the role that female steroid hormones play in the physiological control of
the immune system, and specifically how estrogen could play into such immunological
disorders as Multiple Sclerosis and HIV.
Representative
publications
Bruce, A.J., W.W.
Boling, J. Keller, M. Kindy, J. Peschon and M.P. Mattson (1996) Altered responses
to ischemic and excitotoxic brain injury in transgenic mice lacking tumor necrosis
factor receptors. Nature Medicine. 2: 788-794.
Bruce-Keller,
A.J. and M.P. Mattson (1998) Modulatory role of NFkB in neuronal and glial responses
to injury. In (J. Kreiglestein, Ed) "Proceedings of the 6th International
Symposium on the Pharmacology of Cerebral Ischemia" MedPharm Pub, Inc.,
Stuttgart, 309-317.
Bruce-Keller,
A.J., J.W. Geddes, P.E. Knapp, R.W. McFall, J.N. Keller, S. Parthanathy, S.
Steiner, and M.P. Mattson (1999) Anti-death properties of TNF against metabolic
poisoning: mitochondrial stabilization by MnSOD. J. Neuroimmunol. 93:53-71.
Bruce-Keller, A.J.
R.W. McFall, G.H. Umberger, and M.P. Mattson (1999) Caloric restriction decreases
neuronal vulnerability to excitotoxic and metabolic injury. Ann. Neurol. 45:
8-15.
Bruce-Keller,
A.J. (1999) Microglial - neuronal signaling and synaptic damage and recovery.
In (M.P. Mattson, D. Alkon, and A.J. Bruce-Keller, Eds) "Synaptic Signaling
in Plasticity and Apoptosis" Journal of Neuroscience Research, In Press.
Bruce-Keller,
A.J., J.L. Keeling, J.N. Keller, F.F. Huang, S. Camondola, and M.P. Mattson
(2000) Anti-inflammatory properties of estrogen on microglial activation. Endocrinology
141: 3646-3656.
Bruce-Keller,
A.J., S.W. Barger, N. Moss, J. Pham, J.N. Keller, and A. Nath (2001) Pro-inflammatory
and pro-oxidant properties of the HIV protein Tat in microglia: attenuation
by 17b-estradiol. J. Neurochem. J. Neurochem. 78: 1315-1324, 2001.
Bruce-Keller,
A.J. and Estus, S. Concern over the amyloid vaccine: amyloid
heterogeneity and Fc receptor signaling. Neurobiology of Aging 23:
677-678,
2002.
repertoire
of cellular responses to defend the brain from external threats, including the
ability to secrete low-molecular weight neurotoxins, free radicals, and complement
factors; as well as the ability to phagocytize foreign bodies and damaged tissue.
However, based on the extreme cytotoxic potential of these neuro-inflammatory
pathways, it can proposed that prolonged microglial activation in the brain
contributes to (if not carries) brain injury, and should be pharmacologically
abated. Hence, plummeting estrogen levels in post-menopausal women may be a
factor in the development of AD by allowing for unchecked microglial activation.
This association between estrogen and microglial activation may partially explain
why both estrogen replacement therapy and long-term anti-inflammatory drug therapy
decreases a women’s risk for AD.
Additionally,
estrogen has extremely potent effects on the immune system, as evidencedby both
the increased prevalence of autoimmune disorders in women and in the alterations
in humoral immunity during pregnancy. We have recently become very interested
in the role that female steroid hormones play in the physiological control of
the immune system, and specifically how estrogen could play into such immunological
disorders as Multiple Sclerosis and HIV.