Increased Number of Plasma B Cells Producing Autoantibodies Against Aß42 Protofibrils in Alzheimer's Disease.

The Alzheimer's disease (AD)-related peptide amyloid-ß (Aß) has a propensity to aggregate into various assemblies including toxic soluble Aß protofibrils. Several studies have reported the existence of anti-Aß antibodies in humans. However, it is still debated whether levels of anti-Aß antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma Aß makes it difficult to reliably measure the concentration of circulating anti-Aß antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-Aß antibody production on a cellular level by measuring the amount of anti-Aß antibody producing cells instead of the plasma level of anti-Aß antibodies. To our knowledge, this is the first time the anti-Aß antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding Aß40 monomers, whereas the number of cells producing antibodies toward Aß42 protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic Aß protofibrils, which is significantly increased in AD patients.

Docosahexaenoic acid stabilizes soluble amyloid-beta protofibrils and sustains amyloid-beta-induced neurotoxicity in vitro.

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-beta (Abeta) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with Abeta, and their effect on Abeta 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 Abeta42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-beta-induced toxicity in PC12 cells over time, whereas Abeta without docosahexaenoic acid stabilization resulted in reduced toxicity, as Abeta formed fibrils. Arachidic acid had no effect on Abeta aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on Abeta42 harboring the Arctic mutation (AbetaE22G). Consequently, AbetaArctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different Abeta aggregates and how endogenous lipids can affect Abeta aggregation.