与tau 病理和认知障碍相关的与年龄相关的钙失调在非人类灵长类动物中。

Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates.

机构信息

Departments of Neuroscience, School of Medicine, Yale University, Connecticut, USA.

Department of Psychiatry, School of Medicine, Yale University, Connecticut, USA.

出版信息

Alzheimers Dement. 2021 Jun;17(6):920-932. doi: 10.1002/alz.12325. Epub 2021 Apr 7.

INTRODUCTION

The etiology of sporadic Alzheimer's disease (AD) requires non-genetically modified animal models.

METHODS

The relationship of tau phosphorylation to calcium-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno-electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques.

RESULTS

Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808-RyR2). Calcium also regulated early tau phosphorylation in vitro. Age-related reductions in the calcium-binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques.

DISCUSSION

Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.

简介

散发性阿尔茨海默病（AD）的病因需要非遗传修饰的动物模型。

方法

使用生物化学和免疫电子显微镜分析衰老恒河猴外侧前额叶皮层（dlPFC）和大鼠原代皮质神经元中海马钙循环腺苷单磷酸（cAMP）-蛋白激酶 A（PKA）失调与 tau 磷酸化的关系。在老年猕猴中研究ryanodine 受体（RyRs）钙泄漏对神经元放电和认知表现的影响。

结果

自然衰老的猴子会出现过度磷酸化的 tau，包括 AD 生物标志物（AT8（pS202/pT205 和 pT217）和 pT217）和早期 tau 病理标志物（pS214 和 pS356），这些标志物与钙泄漏增加的证据（pS2808-RyR2）相关。钙还在体外调节早期 tau 磷酸化。在 dlPFC 锥体神经元树突内观察到与年龄相关的钙结合蛋白钙调蛋白和磷酸二酯酶 PDE4D 的减少。用 S107 阻断 RyRs 可改善老年猕猴的神经元放电和认知表现。