Ageing – a changing environment in the brain leads to deteriorating synaptic function

2004

YEAR BOOK

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Trinity College Dublin

Marina Lynch

Ageing – a changing environment in the brain leads to deteriorating synaptic function

Until 10 or so years ago the brain was considered to be an immune-privileged organ, but since then it has become clear that this view is untenable. We now know that several cytokines which modulate immune function are synthesized in brain tissue, both in neurons and glia. Various stresses (e.g. oxidative stress, infection, injury) trigger these cells to release proinflammatory cytokines like interleukin-1beta (IL-1beta), which initiate a cascade of reactions leading to deterioration of cell function and, in certain circumstances, cell death. IL-1beta concentration is increased in the hippocampus of aged rats and this significantly contributes to the age-related impairment in synaptic function, specifically the deficit in long-term potentiation (LTP), a model for learning and memory.

Recent evidence has indicated that the increased IL-1beta concentration is accompanied by a decrease in hippocampal concentration of the anti-inflammatory cytokines, IL-10 and IL-4, which protect hippocampal cells from the detrimental effects of IL-1beta and block the IL-1beta-induced impairment of LTP. We predicted that if the age-related decreases in IL-4 and/or IL-10 could be prevented or reversed, then the detrimental effects of the increase in IL-1beta concentration could be abrogated, and therefore we have been attempting to identify strategies which might enhance hippocampal concentrations of IL-4 or IL-10 in the aged brain. Recent studies have established that the polyunsaturated fatty acids, eicosapentaenoic acid (an n-3 fatty acid found in fish oil) and, to a lesser extent, gamma-linolenic acid (an n-6 fatty acid found in evening primrose and starflower oils), increase the concentration of both IL-4 and IL-10, and that enriching the diet of aged rats with these polyunsaturated fatty acids reverses the age-related deficit in LTP.

The steroid dexamethasone is a potent anti-inflammatory agent which has been shown to downregulate expression of proinflammatory cytokines like IL-1beta in peripheral cells where its actions have been comprehensively studied. We treated aged rats with dexamethasone and vitamin D3, which has been shown to increase production of anti-inflammatory cytokines, and assessed the ability of these rats to sustain LTP. Our data indicated that treatment with dexamethasone and vitamin D3 reversed the age-related deficit in LTP and, in parallel, reversed the age-related increase in IL-1beta concentration in the hippocampus. Analysis of IL-10 concentration suggested that a key factor underlying these changes was an increase in the concentration of this anti-inflammatory cytokine in hippocampal tissue, reversing the age-related decrease which was observed in untreated aged rats.

Our current work is focussing on establishing the mechanism by which the anti-inflammatory cytokines act to protect hippocampal cells from IL-1beta-induced damage.

Contact: Professor Marina Lynch, Institute of Neuroscience and Physiology Department, Trinity College, Dublin 2;
E-mail: [email protected]