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Natural oligomers of the amyloid-β protein specifically disrupt cognitive function

Abstract

A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-β protein interferes with cognitive function. Soluble oligomeric forms of amyloid-β, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although β-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.

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Figure 1: Conditioned medium from cells secreting human amyloid-β oligomers and monomers disrupts learned behavior.
Figure 2: Oligomers but not monomers of amyloid-β disrupt learned behavior.
Figure 3: Rats continue to learn the behavioral task during chronic intermittent exposure to amyloid-β oligomers.
Figure 4: The disruptive effect of amyloid-β oligomers on learned behavior is potent.

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Acknowledgements

We thank S. Lesné, J. Huard and M. Podlisny for critical discussions. We are grateful to J. Fadeeva and V. Betts for technical assistance. These studies were funded by the Minnesota Medical Foundation (K.H.A.), the Mayo Medical Foundation (K.H.A.), the US National Institutes of Health (K.H.A., D.J.S.) and the Wellcome Trust (D.M.W.). K.H.A. is a member of the Scientific Advisory Board of Acumen Pharmaceuticals.

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Correspondence to Karen H Ashe.

Supplementary information

Supplementary Fig. 1

Running response rates at each ratio response requirement value. Running response rate is the rate of responding on either lever, in responses per minute, occurring while a subject is actively pressing levers. Time spent eating and post-reinforcement pauses are not counted in this activity measure. Running response rate is a direct function of the size of the response requirement. No significant differences in running response rate were found under ICV injections of 7PA2 CM (triangles) or A βoligomers (squares) when tested against baseline running response rates (diamonds) at any ratio value. Overall response rates (total responses / session time) were also not significantly different (data not shown). Brackets are 1 SEM. (PDF 219 kb)

Supplementary Fig. 2

(A) 7PA2 and CHO cells were metabolically labelled with 35S-methionine for 16 h and the CM collected, cleared of cells and used for R1282 IP and autoradiography. Only p3, A β monomer, dimers and trimers are specifically detected in 7PA2, and not CHO CM. (B) Full gel view of our original Fig. 1 (A). 7PA2 and CHO CM were IP’d with R1282, the IP stored and the supernatant IP’d a second time. The first and second IPs were then examined by Western blotting using 6E10. As in (A), A β monomer, dimers and trimers are specifically detected in 7PA2, and not CHO CM. (PDF 248 kb)

Supplementary Fig. 3

(A) Incubation of 7PA2 CM in CSF at 37°C for 150? minutes results in no significant decrease in 7PA2-derived monomeric Aβ. 7PA2 cells were metabolically labeled with 35S-methionine for 16 h and the conditioned medium (CM) collected and cleared of cells. This CM was used as a source of labeled Aβ: aliquots of 35S-met 7PA2 CM (1 ml) were added to human cerebrospinal fluid (CSF) (20 ml) in the presence of proteases inhibitors and incubated at 4°C or else incubated without protease inhibitors at 37°C. After 160 min the CM/CSF mixtures were then IP’d with R1282 and the immunoprecipitate electrophoresed on 10-20% tricine gels and subjected to autoradiography. (B Incubation of CSF at 37°C for 150 minutes results in no significant decrease in endogenous monomeric Aβ. Human (4 ml) or ovine (2.5 ml) CSF was incubated at either 4°C or 37°C for 150 min and monomeric Aβ content determined by immunoprecipitation with R1282 and subsequent Western blotting with 6E10. Artificial CSF (ACSF), which does not contain Aβ was used as a negative control (PDF 453 kb)

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Cleary, J., Walsh, D., Hofmeister, J. et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci 8, 79–84 (2005). https://doi.org/10.1038/nn1372

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