Iron is increased in the brains of ageing mice lacking the neurofilament light gene

PLoS One. 2019 Oct 23;14(10):e0224169. doi: 10.1371/journal.pone.0224169. eCollection 2019.

Abstract

There has been strong interest in the role of metals in neurodegeneration, and how ageing may predispose the brain to related diseases such as Alzheimer's disease. Recent work has also highlighted a potential interaction between different metal species and various components of the cytoskeletal network in the brain, which themselves have a reported role in age-related degenerative disease and other neurological disorders. Neurofilaments are one such class of intermediate filament protein that have a demonstrated capacity to bind and utilise cation species. In this study, we investigated the consequences of altering the neurofilamentous network on metal ion homeostasis by examining neurofilament light (NFL) gene knockout mice, relative to wildtype control animals, at adulthood (5 months of age) and advanced age (22 months). Inductively coupled plasma mass spectroscopy demonstrated that the concentrations of iron (Fe), copper (Cu) and zinc (Zn) varied across brain regions and peripheral nerve samples. Zn and Fe showed statistically significant interactions between genotype and age, as well as between genotype and region, and Cu demonstrated a genotype and region interaction. The most substantial difference between genotypes was found in Fe in the older animals, where, across many regions examined, there was elevated Fe in the NFL knockout mice. This data indicates a potential relationship between the neurofilamentous cytoskeleton and the processing and/or storage of Fe through ageing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Aging / pathology*
  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Gene Expression Regulation, Developmental*
  • Homeostasis
  • Iron / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurofilament Proteins / physiology*
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / pathology*

Substances

  • Neurofilament Proteins
  • neurofilament protein L
  • Iron

Grants and funding

This work was funded by the J.O. and J.R. Wicking Trust (Equity Trustees). The Florey Institute of Neuroscience and Mental Health acknowledge the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant. Author Paul Adlard is a paid consultant and shareholder in Alterity Therapeutics, which is pursuing therapeutic agents based on metal biology. The specific roles of these authors are articulated in the ‘author contributions’ section. Alterity Therapeutics had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.