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

痴呆症是广泛的神经退行性过程的临床高潮，导致认知功能丧失。在人类中，痴呆症的风险随着年龄的增长而逐渐增加，因此预计由于预期寿命的延长，痴呆症将对健康和社会保健造成越来越大的负担。阿尔茨海默病（AD）是最常见的痴呆形式之一，其中潜在的原因被认为是淀粉样蛋白-β（Abeta）和高磷酸化tau（ptau）的错误折叠和积累，伴有神经炎症。遗传学研究还鉴定了几种基因的变体，例如编码ApoE α 4、早老素-1和早老素-2的基因，这些基因与发展AD的较高风险相关。然而，AD神经病理学进展的确切机制仍有争议。比较医学是对不同物种的病理生理过程的研究，可以识别疾病的保守和不同的分子途径。这些研究对于了解每个物种共有或独特的生物学至关重要，但也有可能产生预防和治疗疾病的新方法的想法。小鼠模型在AD研究中发挥着重要作用，但通过研究寿命更长的物种中与年龄相关的神经病理学，可以获得更多的见解，这些物种的大脑结构与人类更相似。猫和羊是已知在老年个体的大脑中积累Abeta和ptau的唯一物种，如在人类AD患者中，并且在老年猫中，一种形式的猫痴呆症（称为猫认知功能障碍）是众所周知的。然而，我们缺乏对这些物种的神经退行性过程和遗传风险因素的详细了解。此外，猫和羊在生理和环境上有明显的不同，我们假设它们在与年龄相关的神经退行性疾病的发展上也有显着的差异。该项目将使用各种方法，包括组织病理学，蛋白质生物化学（包括蛋白质组学）和DNA测序，对猫和羊的年龄相关神经病理学过程和潜在易感遗传因素进行深入比较。我们可以访问不同年龄组的猫和羊在其整个生命周期中的大脑的独特档案。该项目将加深对不同物种大脑衰老基本机制的理解，并为人类和家猫开发新疗法提供靶向途径信息。

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.