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Docosahexaenoic acid stabilizes soluble amyloid-β protofibrils and sustains amyloid-β induced neurotoxicity in vitro
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
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2007 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 274, no 4, 990-1000 p.Article in journal (Refereed) Published
Abstract [en]

Enrichment of diet and culture media with the polyunsaturated fatty acid docosahexaenoic acid has been found to reduce the amyloid burden in mice and lower amyloid-β (Aβ) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with Aβ, and their effect on Aβ aggregation has not been explored in detail. Therefore, we have investigated the effect of docosahexaenoic acid, arachidonic acid and the saturated fatty acid arachidic acid on monomer oligomerization into protofibrils and protofibril fibrillization into fibrils in vitro, using size exclusion chromatography. The polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid at micellar concentrations stabilized soluble Aβ42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-β-induced toxicity in PC12 cells over time, whereas Aβ without docosahexaenoic acid stabilization resulted in reduced toxicity, as Aβ formed fibrils. Arachidic acid had no effect on Aβ aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on Aβ42 harboring the Arctic mutation (AβE22G). Consequently, AβArctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different Aβ aggregates and how endogenous lipids can affect Aβ aggregation.

Place, publisher, year, edition, pages
2007. Vol. 274, no 4, 990-1000 p.
Keyword [en]
amyloid-β, docosahexaenoic acid, micelles, neurotoxicity, protofibrils
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95579DOI: 10.1111/j.1742-4658.2007.05647.xISI: 000243940800009PubMedID: 17227385OAI: oai:DiVA.org:uu-95579DiVA: diva2:169855
Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2011-02-15Bibliographically approved
In thesis
1. Amyloid-β Protofibril Formation and Neurotoxicity: Implications for Alzheimer’s Disease
Open this publication in new window or tab >>Amyloid-β Protofibril Formation and Neurotoxicity: Implications for Alzheimer’s Disease
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is the most common cause of dementia. A characteristic feature of AD is the presence of amyloid plaques in the cortex and hippocampus of the brain. The principal component of these plaques is the amyloid-β (Aβ) peptide, a cleavage product from proteolytic processing of amyloid precursor protein (APP). A central event in AD pathogenesis is the ability of Aβ monomers to aggregate into amyloid fibrils. This process involves the formation of various Aβ intermediates, including protofibrils. Protofibrils have been implicated in familial AD, as the Arctic APP mutation is associated with enhanced rate of protofibril formation in vitro.

This thesis focuses on Aβ aggregation and neurotoxicity in vitro, with special emphasis on protofibril formation. Using synthetic Aβ peptides with and without the Arctic mutation, we demonstrated that the Arctic mutation accelerated both Aβ1-42 protofibril- and fibril formation, and that these processes were affected by changes in the physiochemical environment.

Oxidation of Aβ methionine delayed trimer and protofibril formation in vitro. Interestingly, these oxidized peptides did not have the neurotoxic potential of their un-oxidized counterparts, suggesting that formation of trimers and further aggregation into protofibrils is necessary for the neurotoxic actions of Aβ. In agreement, stabilization of Aβ wild type protofibrils with the omega-3 (ω3) fatty acid docosahexaenoic acid (DHA) sustained Aβ induced neurotoxicity; whereas in absence of DHA, neurotoxicity was reduced as Aβ fibrils were formed. These results suggest that the neurotoxic potential of Aβ is mainly confined to soluble aggregated forms of Aβ, not Aβ monomer/dimers or fibrillar Aβ.

Stabilization of Aβ protofibrils with DHA might seem contradictory, as ω3 fatty acids generally are considered beneficial for cognition. However, we also demonstrated that DHA supplementation reduced Aβ levels in cell models of AD, providing a possible mechanism for the reported beneficial effects of DHA on cognitive measures in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 239
Neurosciences, Amyloid-β, Neurotoxicity, Aggregation, Protofibrils, Alzheimer's disease, Neurovetenskap
urn:nbn:se:uu:diva-7718 (URN)978-91-554-6827-9 (ISBN)
Public defence
2007-04-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2007-03-23 Created: 2007-03-23 Last updated: 2011-01-27Bibliographically approved

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Johansson, Ann-SofiKarlsson, GöranEdwards, KatarinaLannfelt, Lars
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