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Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone

Abstract

We previously reported1 the presence of amyloid-β protein (Aβ) deposits in individuals with Creutzfeldt–Jakob disease (CJD) who had been treated during childhood with human cadaveric pituitary-derived growth hormone (c-hGH) contaminated with prions. The marked deposition of parenchymal and vascular Aβ in these relatively young individuals with treatment-induced (iatrogenic) CJD (iCJD), in contrast to other prion-disease patients and population controls, allied with the ability of Alzheimer’s disease brain homogenates to seed Aβ deposition in laboratory animals, led us to argue that the implicated c-hGH batches might have been contaminated with Aβ seeds as well as with prions. However, this was necessarily an association, and not an experimental, study in humans and causality could not be concluded. Given the public health importance of our hypothesis, we proceeded to identify and biochemically analyse archived vials of c-hGH. Here we show that certain c-hGH batches to which patients with iCJD and Aβ pathology were exposed have substantial levels of Aβ40, Aβ42 and tau proteins, and that this material can seed the formation of Aβ plaques and cerebral Aβ−amyloid angiopathy in intracerebrally inoculated mice expressing a mutant, humanized amyloid precursor protein. These results confirm the presence of Aβ seeds in archived c-hGH vials and are consistent with the hypothesized iatrogenic human transmission of Aβ pathology. This experimental confirmation has implications for both the prevention and the treatment of Alzheimer’s disease, and should prompt a review of the risk of iatrogenic transmission of Aβ seeds by medical and surgical procedures long recognized to pose a risk of accidental prion transmission2,3.

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Fig. 1: Quantification of vessels with CAA in AppNL-F/NL-F mice following inoculation with Alzheimer’s or control human brain, vehicle alone, or recombinant or cadaveric human growth hormone.
Fig. 2: Quantification of cerebellar plaque area in AppNL-F/NL-F mice inoculated with Alzheimer’s or control human brain, vehicle alone, or recombinant or cadaveric human growth hormone.
Fig. 3: Aβ plaque deposition and CAA in AppNL-F/NL-F mice following inoculation with AD or control brain.
Fig. 4: Aβ plaque deposition and CAA in AppNL-F/NL-F mice following inoculation with cadaveric or recombinant growth hormone preparations.

Data availability statement

Source data for Figs. 1 and 2 are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was funded by the UK Medical Research Council (MRC); the National Institute of Health Research (NIHR) University College London Hospitals (UCLH)/University College London (UCL) Biomedical Research Centre; the Leonard Wolfson Experimental Neurology Centre; and a grant to D.M.W. from the National Institute on Aging (AG046275). We thank the Queen Square Brain Bank for Neurological Disorders (supported by the Reta Lila Weston Trust for Medical Research, the Progressive Supranuclear Palsy (Europe) Association and the MRC) at the UCL Institute of Neurology, University College London; and the Oxford Brain Bank (supported by the MRC, the NIHR Oxford Biomedical Research Centre and the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society) for providing the UK human brain tissue samples. We thank M. Ellis for image analysis; Z. Jaunmuktane for advice on CAA scoring; and G. Graham, C. Fitzhugh, R. Labesse-Garbal and other staff of the MRC Prion Unit Biological Services facility for animal inoculation, observation and care. We thank M. Farmer and E. Quarterman for technical assistance; O. Avwenagha and J. Wadsworth for assistance in selecting and processing tissue samples; and E. Noble for assistance with assay development. We thank P. Adlard for help in identifying growth-hormone batches for this study and M. Sutton for providing c-hGH vials from archived stores at Public Health England Porton Down. Antibodies m266, 2G3 and 21F12 were gifts from P. Seubert and D. Schenk, Elan Pharmaceuticals.

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Authors and Affiliations

Authors

Contributions

S.A.P. and M.A.F. coordinated animal experiments and performed data analysis. J.L., T.N. and S.B. performed neuropathological analysis. D.X.T., Z.C., D.M. and D.M.W. performed and analysed biochemical assays. T.Saito and T.Saido provided NL-F mice. P.R. coordinated the identification and sourcing of relevant archival c-hGH batches. J.C. oversaw the study and drafted the manuscript with contributions from all authors.

Corresponding author

Correspondence to John Collinge.

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Competing interests

J.C. is a shareholder and director of D-Gen Limited, an academic spin-out company working in the field of prion-disease diagnosis, decontamination and therapeutics.

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Extended data figures and tables

Extended Data Fig. 1 Time course of CAA and Aβ deposition in control- and AD-brain-inoculated AppNL-F/NL-F mice.

Mice were inoculated with either control-brain homogenates (ac, gi, mo, su) or AD-brain homogenates (df, jl, pr, vx) and culled at the stated times. Aβ deposition was assessed on sagittal sections (a, d, g, j, m, p, s, v). CAA (b, e, h, k, n, q, t, w) and cerebellar deposition (c, f, i, l, o, r, u, x) were evident only in AD-brain-inoculated animals. Boxes denote areas magnified to the right. Scale bars represent 1.4 mm for whole sections (a, d, g, j, m, p, s, v), 25 µm for CAA (b, e, h, k, n, q, t, w), and 50 µm for the cerebellar region (c, f, i, l, o, r, u, x).

Extended Data Fig. 2 Aβ plaques and CAA in AppNL-F/NL-F mice following inoculation with c-hGH preparations.

AppNL-F/NL-F mice were inoculated with c-hGH batch HWP 42 (a, cf, kn) or HWP 51 (b, gj, or) and culled after 240 days. Aβ deposition was assessed on sagittal sections (a, b). Black and red boxes denote areas magnified to better show cerebellar Aβ deposits (cj) and CAA (kr), respectively, in the middle and lower panels. Scale bars represent 1.1 mm for whole sections (a, b) and 50 µm for the cerebellar region and CAA (cr).

Extended Table 1 c-hGH preparations and batches received by each patient

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Purro, S.A., Farrow, M.A., Linehan, J. et al. Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone. Nature 564, 415–419 (2018). https://doi.org/10.1038/s41586-018-0790-y

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