Eicosapentaenoic acid confers neuroprotection in the amyloid-β challenged aged hippocampus

doi:10.1016/j.neurobiolaging.2006.04.006

Neurobiology of Aging

Volume 28, Issue 6, June 2007, Pages 845-855

https://doi.org/10.1016/j.neurobiolaging.2006.04.006 Get rights and content

Abstract

Among the changes that occur in the hippocampus with age, is a deficit in long-term potentiation (LTP). This impairment is associated with inflammatory changes, which are typified by increased concentration of the pro-inflammatory cytokine interleukin-1β (IL-1β). Activated microglia are the most likely cell source of IL-1β, but data demonstrating an age-related increase in microglial activation is equivocal. Here we demonstrate that the age-related deficit in LTP is accompanied by increased expression of cell surface markers of activated microglia (major histocompatibility complex II and CD40) and increased IL-1β production, and that these changes may be stimulated by interferon-γ. Treatment of aged rats with eicosapentaenoic acid (EPA) attenuates these changes and we suggest that IL-4 mediates the action of EPA. We demonstrate that aged rats exhibit an exaggerated response to intracerebroventricular injection of β-amyloid peptide 1-40 (Aβ). Thus Aβ inhibited LTP in aged, but not young, rats and induced a further increase in hippocampal IL-1β concentration. Of particular significance is the demonstration that EPA protects the aged brain so that the increased vulnerability to Aβ is ameliorated in EPA-treated rats.

Introduction

Inflammatory and oxidative changes are features of the aged hippocampus and there is a tight coupling between these changes and the age-related impairment in long-term potentiation (LTP; see Ref. [22]). There is an inverse relationship between the concentration of the proinflammatory cytokine IL-1β, and LTP [9], [20], [25], [29] and this association has been underscored in a number of experimental conditions; for example in rats treated with lipopolysaccharide (LPS; [18]) or amyloid-β_(1-40) (Aβ; 28) and rats exposed to irradiation [21]. Significantly, treatment of aged rats, LPS-treated rats and irradiated rats with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), abrogated the stress-induced increase in IL-1β concentration and restored LTP. These data and others [1], [3], [4], [26], [36], [42] suggest that EPA exerts an anti-inflammatory effect, although the mechanism by which this occurs has not been established.

It is generally accepted that the primary cell source of IL-1β is activated microglia [5], [16] and therefore it might be predicted that evidence of microglial activation will accompany the age-related increase in hippocampal IL-1β concentration. However, although several studies have reported that increased microglial activation accompanies neurodegenerative changes [2], [7], [34], [38], the evidence indicating an increase in activated microglia in the aged brain is equivocal. Microglial activation is triggered in response to brain injury and infection, and one of the most potent activators of microglia in vitro is interferon-γ (IFNγ; [6], [27], [32]); a similar stimulatory action for IFNγ has not been reported in vivo.

That inflammation is a feature of the aged brain [9], [15], [19], [35] may account for increased susceptibility of the brain to injury with age, which has been described in patients [30], [41] and also in animals [9], [13].

Here we set out to establish whether the impairment in LTP in aged animals was accompanied by evidence of microglial activation and to assess whether aged rats were more vulnerable to the effects of Aβ treatment. We report that there is an age-related increase in microglial activation in the hippocampus, which the evidence suggests is triggered by IFNγ and accompanied by a decrease in IL-4 concentration; we propose that this renders the brain more susceptible to the damaging effects of Aβ. The data shows that treatment of aged rats with EPA decreased hippocampal IFNγ concentration, increased IL-4 concentration and downregulated microglial activation. Consistent with the proposal that this underlying inflammation significantly contributed to the exaggerated effects of Aβ in the aged rat, we observed that EPA treatment attenuated the Aβ-induced impairment in LTP.

Section snippets

Animals

Male Wistar rats (BioResources Unit, Trinity College, Dublin, Ireland) of mean age 4 months (250–350 g) or 22 months (450–550 g) were used in these experiments. Animals were housed in pairs (22 month-old rats) or groups of four to six (4 month-old rats) under a 12-h light schedule, ambient temperature was controlled between 22 and 23 °C and rats were maintained under veterinary supervision throughout the study. These experiments were performed under a license issued by the Department of Health

Results

We demonstrate that microglial activation, assessed in three different ways, was markedly increased in hippocampus of aged, compared with young, rats. Analysis of hippocampal major histocompatibility complex II (MHCII) mRNA revealed a significant age-related increase (Fig. 1A, p < 0.01; ANOVA) and the data show that treatment of aged rats with EPA, reduced this increase in MHCII expression so that the mean values in young rats and aged EPA-treated rats were not significantly different. These data

Discussion

We demonstrate that upregulation of microglial activation, triggered by IFNγ, renders the aged brain more vulnerable to Aβ injection and show that the anti-inflammatory and neuroprotective effects of EPA abrogate this age-related vulnerability.

The data show that microglial activation is increased in the hippocampus of aged rats; this is based on data using three methods of analysis. The increase in MHCII immunoreactivity which we describe, is similar to the reported observation of

Acknowledgements

EPA was a kind gift from the late David Horrobin, Laxdale Ltd. (now called Amarin Neuroscience), UK. R.M. Clarke is a recipient of a Trinity College Ussher Fellowship. The Health Research Board Ireland, Science Foundation Ireland, The Higher Education Authority Ireland, Enterprise Ireland.

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¹: Present address: Conway Institute of Biomolecular & Biomedical Research, University College, Dublin, Dublin, Ireland.

²: Present address: Howard Florey Institute, University of Melbourne, Vic. 3010, Australia.

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Eicosapentaenoic acid confers neuroprotection in the amyloid-β challenged aged hippocampus

Abstract

Introduction

Section snippets

Animals

Results

Discussion

Acknowledgements

Nutrition

Neurochem Int

J Biol Chem

J Biol Chem

Biomed Pharmacother

Neurobiol Aging

Brain Res

J Neuroimmunol

J Biol Chem

J Biol Chem

Neurobiol Aging

J Biol Chem

Med Hypotheses

J Biol Chem

J Biol Chem

Am J Clin Nutr

Polyunsaturated fatty acids, inflammation, and immunity

Lipids

The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat

J Cereb Blood Flow Metab

CD40–CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis

Proc Natl Acad Sci USA

Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system

FASEB J

Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages

Eur J Neurosci