Age-related neurodegeneration and dementia: comparison of neuropathological changes and genetic predisposition in diverse species.

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Dementia is the clinical culmination of a broad range of neurodegenerative processes, resulting in loss of cognitive function. In humans, the risk of dementia progressively increases with advancing age, and it is thus predicted to pose an increasing burden on health and social care due to longer life expectancies. Alzheimer's disease (AD) is one of the most common forms of dementia, in which the underlying cause is thought to be misfolding and accumulation of amyloid-beta (Abeta) and hyperphoshorylated tau (ptau), accompanied by neuroinflammation. Genetic studies have also identified variants of several genes, encoding e.g. ApoE alpha4, presenilin-1 and -2, which are associated with higher risks of developing AD. However, the precise mechanisms underlying the progression of neuropathology in AD are still debated. Comparative medicine is the study of pathophysiological processes across different species, allowing the identification of conserved and divergent molecular pathways of disease. Such studies are fundamental to understanding the biology that is shared or unique to each species, but also have potential to generate ideas for novel approaches to prevention and treatment of diseases. Mouse models have an important role in AD research, but additional insights can be gained by studying age-related neuropathology in species of greater longevity, with brain structures that more closely resemble humans. Cats and sheep are some of the only species known to accumulate both Abeta and ptau in the brains of aged individuals, as in human AD patients, and in older cats a form of feline dementia (known as feline cognitive dysfunction) is well recognized. However, we lack detailed knowledge of the neurodegenerative processes and genetic risk factors in these species. In addition, cats and sheep differ markedly in their physiology and environment and we hypothesize that there will be significant differences in their development of age-related neurodegeneration. The project will perform an in-depth comparison of age-related neuropathological processes and potential predisposing genetic factors in cats and sheep, using a variety of approaches including histopathology, protein biochemistry (including proteomics) and DNA sequencing. We have access to unique archives of brains from cats and sheep of different age groups across their entire lifespan. The project will result in enhanced understanding of fundamental mechanisms of brain senescence across species, and provide information on pathways to target for development of novel therapeutics in both humans and domesticated cats.