Cross-species characterisation of microglial morphology and proliferation during ageing

By 2050, one-fifth of the world is expected to be over 60, and the prevalence of age-related neurological conditions is predicted to increase dramatically. Aged animals are currently underutilised in neurological research, leading to a gap in knowledge about the contribution of biological age to the pathophysiology of age-related neurological conditions. Additionally, it is unclear whether age-related changes differ across species used in preclinical models, and how these differences may compare to the aged human brain. Understanding these points is critical for successful translation of findings from preclinical studies to the human context. The current study presents a cross-species characterisation of microglia, the key regulator of the brain's immune response, during ageing. Microglial number, proliferation and morphology were assessed in archival tissue from Sprague Dawley rats (males; 3 to 18 months old) and Merino sheep (males and females; 1 to 6 years old), with these two species selected for their relevance to preclinical modelling of neurological disease. Increased numbers of proliferating microglia were observed in the cortex, hippocampus and portions of the striatum in both species. This proliferation declined at the oldest timepoint assessed (i.e. 18 months old) in rats, a pattern not seen in the sheep. Total microglial number was largely unchanged with age in the rat brain; however, in sheep, the number of microglia decreased significantly in the dentate gyrus in older animals. Notably, microglia in 18-month-old rats were larger in all regions, but changes in branching were observed exclusively the striatum. Similarly, in sheep, morphological changes were localised to the striatum, with increased cell and soma size in the caudate nucleus, and increased cell size and process length in the putamen. These changes suggest a shift away from homeostasis in the cortex and hippocampus and towards a semi-ramified morphology in the striatum in late middle adulthood that is largely conserved across these two species. Nevertheless, the age of the oldest animals here equates to only ~ 60 years old in humans, rather than reflecting an aged human population. Thus, future work is needed to understand how species-specific differences continue to evolve in older age.