Premium
O2‐02–04: Lipids revert inert amyloid fibrils to neurotoxic protofibrils that affect learning in mice
Author(s) -
Kuperstein Inna,
Martins Ivo,
Wilkinson Hannah,
Vanbrabant Mieke,
Maes Elke,
D'Hooge Rudi,
Schymkowitz Joost,
Rousseau Frederic,
De Strooper Bart
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.316
Subject(s) - neurotoxicity , fibril , chemistry , oligomer , amyloid (mycology) , peptide , biophysics , monomer , sphingomyelin , biochemistry , lipid raft , cholesterol , toxicity , biology , polymer , organic chemistry , inorganic chemistry
Background: Alzheimer's disease (AD) is associated with the aggregation of Amyloid-β peptide (Aβ). It is believed that neurotoxicity is caused during the Aβ aggregation process, by soluble Aβ oligomers species, and not by the Aβ fibrils themselves that considered as inert end-products of the aggregation process. Nevertheless, stability of Aβ fibrils might be overestimated. We found that inert Aβ fibrils can be reversed to toxic oligomers in the presence of synthetic phospholipids and lipid rafts components as gangliosids, sphingomyelin and cholesterol. Interestingly, the equilibrium is not shifted towards monomeric Aβ but rather towards soluble amyloid oligomers (backward oligomers). Methods: Biochemical and biophysical analysis, neurotoxicity study on primary neurons and mice brain icv. injection of amyloid oligomers were performed. Results: Backward oligomers are very similar to the oligomers found during the classical aggregation process of monomeric Aβ (forward oligomers). Backward oligomers cause synaptic markers loss and immediate neurotoxicity to primary neurons followed by apoptotic cell death. In addition, mice brain icv. injection of backward amyloid oligomers causes Tau phosphorylation, Caspase 3 activation and memory impairment in mouse similarly to forward oligomers. Finally, we observe that release of toxic oligomers and subsequent neurotoxicity may be caused by other disease-associated amyloid peptides as TAU, Prion 1 and synthetic amyloidogenic peptide in the presence of lipids. Conclusions: We propose that lipid-induced fibrils disassembly and release of soluble oligomers is a common generic mechanism of amyloids. An important implication of our work is that amyloid plaques are not inert and should be considered as potential large reservoirs of neurotoxic oligomers that can rapidly be mobilized by lipids. Although lipid metabolism has been implicated in neurodegenerative diseases the precise involvement of lipids in basic toxicity mechanisms in AD is a major question. Our data could help to understand this Aβ and lipid relationship in more detailstatus: publishe