Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice

• Ivo Cristiano Martins ^[1] ; Inna Kuperstein ^[2] ; Hannah Wilkinson ^[1] ; Elke Maes ^[2] ; Mieke Vanbrabant ^[2] ; Wim Jonckheere ^[1] ; Patrick Van Gelder ^[3] ; Dieter Hartmann ^[2] ; Rudi D'Hooge ^[4] ; Bart De Strooper ^[2] ; Joost Schymkowitz ^[1] ; Frederic Rousseau ^[1]
  1. [1] Switch Laboratory, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium
  2. [2] Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Institute for Biotechnology (VIB) and KULeuven, Leuven, Belgium
  3. [3] ULTR Laboratory, Department for Molecular and Cellular Interactions, Flanders Institute for Biotechnology (VIB) and Vrije Universiteit Brussel (VUB), Brussel, Belgium
  4. [4] Laboratory of Biological Psychology, KULeuven, Leuven, Belgium

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 27, Nº. 1, 2007, págs. 224-233
• Idioma: inglés
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  • Although soluble oligomeric and protofibrillar assemblies of Aβ-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds ‘forward' in a near-irreversible manner from the monomeric Aβ peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward' Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward' Aβ protofibrils obtained from the aggregation of fresh Aβ monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Aβ-aggregates that could readily be activated by exposure to biological lipids.