Objective
Degeneration of the nervous and immune systems, both in normal ageing and in conditions such as Alzheimer's disease (AD), has been attributed to the lifetime decline in circulating levels of the adrenal steroid debydroepiandrosterone (DHEA). In humans and higher primates, levels of DHEA fall dramatically with age.
Because DHEA improves hippocampus-associated learning and memory in rodents, and markedly improves perceived well-being in middle-aged volunteers, a causal link between falling DHEA levels and age-related cognitive decline including AD has been discussed. Further, DHEA administration clearly improves immune responsiveness of ageing rodents. For these reasons DHEA has been widely and publicly advocated in the therapy of age-related disorders including memory impairment.
However, the mechanism of action of DHEA is unknown. A plausible hypothesis is that DHEA antagonizes glucocorticoid action, because excess glucocorticoids attenuate memory function and promote neurotoxicity in the hippocampus, while having clear immunosuppressive effects. However, DHEA fails to interact with glucocorticoid receptors.
We have previously reported that DHEA and related steroids are selectively metabolized, in brain and other tissues, to modified molecules, predominantly 7a-hydroxy derivatives but including 6 and 7beta-modified derivatives. For many years the enzyme(s) responsible were unknown, but recently we reported the molecular characterization of a novel cytochrome P450 from rodent brain, Cyp7b, that efficiently converts DHEA to 7ahydroxy DHEA (7HD). Further, we have shown that 7HD, unlike its precursor DHEA, is an antagonist of the glucocorticoid response. Moreover, CYP7B mRNA levels are selectively reduced in Alzheimer's disease. We surmise that excess glucocorticoid action brought about by decline in 7HD, accentuated by the lifetime decline in levels of its substrate, lead to neurotoxicity and cognitive decline in normal ageing and prematurely in AD. A similar process is thought to operate in Lymphocytes.
This hypothesis links the decline in lifetime DHEA with reduced inhibition of glucocorticoid action in the brain, concomitant neuronal loss, failure of feedback inhibition in the brain, and escalating neuronal damage and immunosuppression. Because we will use recombinant yeast to produce novel steroids the proposal thus spans several different disciplines; ranging from Area 4: Cell Communication in the Neurosciences (Degeneration of the Nervous System) through to Area 1 (Biological Components of Cell
Factories/Biotransformations).
The present proposal aims towards several objectives.
(1) To identify and characterize other novel P450s responsible for the metabolic conversions of DHEA, estrogen and related steroids in brain and other tissues; to study their substrate specifically and the reactions catalyzed, and to explore the age-profile of their expression.
(2) To use a recombinant yeast system to express novel cytochromes P450 including CYP7B in order to produce, in large quantities, modified derivatives of DHEA, pregnenolone, estradiol and related molecules.
(3) To study the effects of DHEA/estradiol, and their novel metabolites, on (i) cognition in young and ageing rodents (ii) on tumor cell rejection in adult rat models of breast cancer.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences zoology mammalogy primatology
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences basic medicine immunology
- medical and health sciences clinical medicine oncology breast cancer
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Coordinator
EH9 3JQ EDINBURGH
United Kingdom
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