Zinc-amyloid beta interactions on a millisecond time-scale stabilize non-fibrillar Alzheimer-related species.
The role of zinc, an essential element for normal brain function, in the pathology of Alzheimer's disease (AD) is poorly understood. On one hand, physiological and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid beta-protein (Abeta) in senile plaques. On the other hand, levels of extracellular ("free") zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing Abeta aggregation. Remarkably, the release of transient high local concentrations of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting Abeta aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concentrations, immediately interacts with Abeta 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of Abeta fibrils (more benign species) presumably by interfering with the self-assembly process of Abeta. These in vitro results strongly suggest a significant role for zinc pulses in Abeta pathology. We further propose that by interfering with Abeta self-assembly, which leads to insoluble, non-pathological fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of molecular pathogens that effectively perturb the self-assembly of benign Abeta fibrils, and stabilize harmful non-fibrillar forms.
Noy
Dror
D
Structural Biology Department and Electron Microscopy Unit, Weizmann Institute of Science, Rehovot 76100, Israel.
Solomonov
Inna
I
Sinkevich
Ory
O
Arad
Talmon
T
Kjaer
Kristian
K
Sagi
Irit
I
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001921:Brain / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008956:Models, Chemical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D012542:Scattering, Radiation; D013053:Spectrophotometry / Q000379:methods; D013997:Time Factors; D014961:X-Ray Diffraction; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D010455:Peptides; D015032:Zinc