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.
Highlights
Divalent cation metal species such as zinc, iron and copper have important normal cellular functions in the nervous system, but may be involved in pathological processes underlying neurodegenerative diseases such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) [1,2,3]
Metal ions have been implicated in many aspects of the AD cascade [4], including a potentially central role in the aggregation of the two primary pathological hallmarks of AD, the beta amyloid plaques and neurofibrillary tangles [5]
Major proteins implicated in neurodegenerative diseases such as the amyloid precursor protein (APP), tau and alpha-synuclein and tau have been shown to be involved
Summary
Divalent cation metal species such as zinc, iron and copper have important normal cellular functions in the nervous system, but may be involved in pathological processes underlying neurodegenerative diseases such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) [1,2,3]. Metal ions have been implicated in many aspects of the AD cascade [4], including a potentially central role in the aggregation of the two primary pathological hallmarks of AD, the beta amyloid plaques and neurofibrillary tangles [5]. In this regard, major proteins implicated in neurodegenerative diseases such as the amyloid precursor protein (APP), tau and alpha-synuclein and tau have been shown to be involved. Alterity Therapeutics, which is pursuing therapeutic agents based on metal biology. Alterity Therapeutics had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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