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

Nature. 2018 Dec;564(7736):415-419. doi: 10.1038/s41586-018-0790-y. Epub 2018 Dec 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced*
  • Alzheimer Disease / etiology
  • Amyloid beta-Peptides / analysis
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / administration & dosage
  • Amyloid beta-Protein Precursor / adverse effects
  • Animals
  • Cadaver*
  • Case-Control Studies
  • Creutzfeldt-Jakob Syndrome / chemically induced*
  • Creutzfeldt-Jakob Syndrome / etiology
  • Disease Models, Animal
  • Disease Transmission, Infectious / prevention & control
  • Disease Transmission, Infectious / statistics & numerical data
  • Drug Contamination* / prevention & control
  • Drug Contamination* / statistics & numerical data
  • Female
  • Growth Hormone / administration & dosage
  • Growth Hormone / pharmacology*
  • Humans
  • Iatrogenic Disease*
  • Male
  • Mice
  • Models, Biological
  • Prions / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Reproducibility of Results
  • tau Proteins / analysis
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Prions
  • Recombinant Proteins
  • tau Proteins
  • Growth Hormone