Docosahexaenoic acid reduces amyloid-β induced toxicity in cells of the neurovascular unit.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta peptides (A beta) as perivascular deposits and senile plaques in the brain. The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and reduced risk in AD in several epidemiological trials; however the exact underlying molecular mechanism remains to be elucidated. The aim of the study was to test whether DHA can exert a direct protective effect on the elements of the neurovascular unit, such as neurons, glial cells, brain endothelial cells, and pericytes, treated with A beta(42) (15 mu M). A dose-dependent high cellular toxicity was found in viability assays in all cell types and on acute hippocampal slices after treatment with A beta(42) small oligomers prepared in situ from an isopeptide precursor. The cell morphology also changed dramatically in all cell types. In brain endothelial cells, damaged barrier function and increased para- and transcellular permeability were observed after peptide treatment. The production of reactive oxygen species was elevated in pericytes and endothelial and glial cells. DHA (30 mu M) significantly decreased the A beta(42)-induced toxic effects in all cell types measured by viability assays, and protected the barrier integrity and functions of brain endothelial cells. DHA also decreased the elevated rhodamine 123 accumulation in brain endothelial cells pre-treated with A beta(42) indicating an effect on efflux pump activity. These results indicate for the first time that DHA can protect not only neurons but also the other elements of the neurovascular unit from the toxic effects of A beta(42) and this effect may be beneficial in AD.