Title: Naked neurones: how does the naked mole-rat brain stay healthy during ageing?
Funder: Dunhill Medical Trust

Abstract: Cognitive decline and neuronal death occur naturally with ageing and age is a key risk factor for many neurodegenerative conditions. Faced with a global ageing population, it is important to further understanding of how the brain ages and what goes wrong in neurodegenerative conditions. The naked mole-rat (NMR, Heterocephalus glaber) exhibits healthy ageing and lives in excess of 30-years, having a mortality rate that defies Gompertzian laws by not increasing with age. Specifically, NMR brains show high accumulation of disease associated moieties like amyloid beta and we have shown them to be resistant to hypoxia, which, combined with the genomic instability inducing effects of accumulative reactive oxygen species (ROS), is a common contributor to many neurodegenerative conditions. We hypothesise that NMR neurones are intrinsically resistant to the damaging effects of pathogenic moieties like amyloid beta and ROS. To test this hypothesis, we will deploy primary neurones and use our established protocols for deriving the first NMR haploid embryonic stem cells (hESC) that can be differentiated to a variety of neuronal subtypes, as well as growing organoids. In these systems, we will use a multidisciplinary approach to measure comparative differences between mouse, human and NMR neurones: • Electrophysiology, to determine differential changes in parameters governing neuronal excitability in response to neurodegeneration associated moieties such as amyloid beta and ROS. Moreover, we will measure the effects of these factors on specific ion channels, such as the transient receptor potential (TRP) ion channel family that is particularly susceptible to lipid modulation and whose function has been linked to longevity and memory. • Atomic force microscopy, ROS activity and moieties, such as amyloid beta, interact with and modulate lipid membranes, we will determine differential effects of these factors upon lipid membrane integrity in mouse and NMR neurones as compared to human, with the hypothesis that NMR cell membranes play a protective role from ROS and neurodegeneration • CRISPR/Cas9 screening of hESC-derived neurones, for identifying candidate genes contributing to neuronal fitness and robustness in response to neurodegeneration associated risk factors, e.g. ROS • Organoids, a more intact system for validating the roles of genes identified through cell-based screening and for looking at the impact of ageing associated risk factors like ROS on neurocircuitry. In summary, we will identify neuroprotective factors and pathways that support sustained neuronal health and genome stability in a long-lived mammal to provide insight into the normal mechanisms of ageing and neurodegeneration.

Lay abstract: Ageing is a natural phenomenon and as we age the probability of something going wrong in the body increases. For example, the likelihood of developing a neurodegenerative brain disorder like Alzheimer’s or Parkinson’s disease increases as we age. Unfortunately, our current understanding of mechanisms underpinning the decline in health with ageing is limited. However, the UK is faced with an ageing population (almost 25% of the UK population will be aged 65+ in 2040) and thus it is ever more pressing to further our knowledge in attempts to development methods for circumventing diseases associated with old age. For most mammals, life expectancy increases with size, e.g. mice weigh ~30 grams and live for ~2-years, whereas African bush elephants, weighing in at excess of 3 tonnes, live ~75-years. The naked mole-rat (NMR) breaks this trend by weighing ~40 grams and yet living in excess of 30-years. Importantly, NMRs exhibit healthy ageing and do not develop age-associated neurodegenerative conditions observed in humans. By understanding how the NMR brain stays healthy throughout its lifespan and does not become damaged by substances associated with neurodegenerative conditions in humans, we will enhance fundamental understanding of how the brain works and provide insight into how to potentially treat ageing-associated neurodegenerative conditions in humans. In a multidisciplinary team, composed of a neuropharmacologist, a neuroscientist and a biophysicist, we will use a range of techniques to establish mechanisms supporting the robustness of neuronal health in the NMR brain compared to the short-lived mouse. In brief, we will measure differential changes in neuronal excitability between mouse and NMR neurones when exposed to factors known to be associated with neurodegenerative conditions in humans. We will also employ a method that enables measurement of cell membrane integrity is altered by such neurodegenerative risk factors – the cell membrane is critical for controlling cellular health and thus anything that impinges on its ability to function as an effective barrier can cause cells to die. We will also use neuronal cell lines and gene editing technology to screen for genes that contribute to neuronal health in response to ageing-associated risk factors and then validate these in more complex systems. In summary, by studying the unique neurobiology of the long-lived NMR, we will significantly advance our understanding of mechanisms governing neuronal health and gain insight into how to what goes wrong in neurodegenerative conditions.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL