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An ancient conserved role for prion protein in learning and memory

机译：ancient病毒蛋白在学习和记忆中的古老保守作用

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The misfolding of cellular prion protein (PrPC) to form PrP Scrapie (PrPSc) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrPCfunction in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrPCin healthy brains is key. Disrupting PrPCin mice has led to a myriad of controversial functions that sometimes map onto disease symptoms, including a proposed role in memory or learning. Intriguingly, PrPCinteraction with amyloid beta (Aβ) oligomers at synapses has also linked its function to Alzheimer's disease and dementia in recent years. We set out to test the involvement of PrPCin memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline inprp2?/?zebrafish, pointing to a conserved and ancient role of PrPCin memory. Specifically, we found that aged (3-year-old)prp2?/?fish performed poorly in an object recognition task relative to age-matchedprp2+/+fish or 1-year-oldprp2?/?fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old)prp2?/?fish approached the novel object more than either age-matchedprp2+/+fish or 1-year-oldprp2?/?fish, but did not have decreased anxiety when we tested them in a novel tank diving test. Taken together, the results of the NOA and novel tank diving tests suggest an altered cognitive appraisal of the novel object in the 3-year-oldprp2?/?fish. The learning paradigm established here enables a path forward to study PrPCinteractions of relevance to Alzheimer's disease and prion diseases, and to screen for candidate therapeutics for these diseases. The findings underpin a need to consider the relative contributions of loss- versus gain-of-function of PrPCduring Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies.
机译：细胞病毒蛋白（PrPC）的错误折叠形成PrP Scrapie（PrPSc）是毒性功能获得机制的典范，该机制导致传播的蛋白错误折叠和进行性破坏性神经变性。尽管如此，在病毒疾病进展期间，大脑中的PrPC功能也会降低和破坏。因此，了解PrPCin健康大脑的正常功能是关键。破坏PrPCin小鼠导致了许多有争议的功能，这些功能有时会映射到疾病症状上，包括在记忆或学习中的拟议作用。有趣的是，近年来，PrPC与淀粉样β（Aβ）寡聚体的相互作用也将其功能与阿尔茨海默氏病和痴呆症联系在一起。我们着手使用不同的动物模型斑马鱼测试PrPCin记忆的参与。在这里，我们记录了inprp2？/？斑马鱼的年龄依赖性记忆衰退，指出了PrPCin记忆的保守和古老作用。具体地，我们发现，相对于年龄匹配的prp2 + / +鱼或1岁的prp2α/β鱼，老的（3岁）prp2α/β鱼在对象识别任务中表现较差。此外，使用新颖对象方法（NOA）测试，我们发现年龄（3岁）的prp2α/β鱼比年龄匹配的prp2 + / +鱼或1岁年龄的prp2α/β鱼更接近新对象。鱼，但是当我们在新型的水箱潜水测试中测试它们时，焦虑并没有减轻。两者合计，NOA和新型水箱潜水测试的结果表明，对3岁的prp2？/？鱼中新物体的认知评估发生了变化。此处建立的学习范例为研究与阿尔茨海默氏病和病毒疾病相关的PrPC相互作用提供了一条途径，并筛选出针对这些疾病的候选疗法。这些发现强调了需要考虑阿尔茨海默氏病和病毒疾病期间PrPC功能丧失与功能获得的相对贡献，并且对几种有前途的治疗策略的前景产生了影响。

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