Affiliations: [a] Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary | [b] Department of Medical Chemistry, University of Szeged, Szeged, Hungary | [c] Division of Pharmacology and Drug Safety Research, Gedeon Richter Plc., Budapest, Hungary | [d] Institute of Experimental Medicine of the Hungarian Academy of Sciences, Budapest, Hungary
Correspondence:
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Correspondence to: Mária A. Deli, M.D., Ph.D., D.Sc., Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary. Tel.: +36 62 599602; Fax: +36 62 433133; E-mail: [email protected].
Abstract: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptides (Aβ) 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 Aβ42 (15 μM). A dose-dependent high cellular toxicity was found in viability assays in all cell types and on acute hippocampal slices after treatment with Aβ42 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 μM) significantly decreased the Aβ42-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 Aβ42 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 Aβ42 and this effect may be beneficial in AD.
