Investigating neuronal hyperactivity as a link between amyloid-beta and tau spreading in Alzheimer's disease (NeurActAmy)

在阿尔茨海默病(AD)中，tau的淀粉样β相关聚集会触发神经退行性变和认知功能下降；因此，防止tau聚集是一个关键的治疗目标。临床前研究发现：1)淀粉样β蛋白导致神经元过度活跃；2)神经元过度活跃促进可溶性过度磷酸化tau(p-tau)种子的突触释放；3)p-tau种子通过突触扩散，导致tau聚集。同样，我们对AD患者的研究表明，与淀粉样β蛋白相关的可溶性p-tau的增加介导了tau在相互连接的大脑区域的扩散。因此，我们假设，淀粉样β蛋白驱动神经元过度活动，触发p-tau增加，随后在AD中通过连接介导tau扩散。因此，减弱与淀粉样β蛋白相关的神经元过度活动可能会限制p-tau的释放、tau的聚集和认知能力的下降。为了验证这一假设，我们将进行一项转换研究项目，将临床AD数据集与神经成像、流体生物标记物、电生理学和患者来源的神经细胞模型相结合。有了这些翻译数据，我们将评估淀粉样β蛋白、神经元过度活动、p-tau增加和tau在连接的神经元/大脑区域中扩散之间的机制联系。我们的发现对于评估神经元活性作为潜在的治疗靶点(例如，通过改变批准的抗癫痫药物的用途)以防止tau扩散、神经退行性变和认知能力下降至关重要。这项工作将有助于为未来针对AD疾病修改的神经元超兴奋性的临床试验提供信息。

In Alzheimer's disease (AD), the amyloid-beta-associated aggregation of tau triggers neurodegeneration and cognitive decline; hence, preventing tau aggregation is a key therapeutic target. Preclinical research found that i) amyloid-beta precipitates neuronal hyperactivity, ii) neuronal hyperactivity promotes synaptic release of soluble hyperphosphorylated tau (p-tau) seeds, and iii) p-tau seeds spread across synapses, ensuing tau aggregation. Similarly, our research in AD patients shows that amyloid-beta-related soluble p-tau increase mediates tau spreading across interconnected brain regions. Therefore, we hypothesize that amyloid-beta drives neuronal hyperactivity, triggering p-tau increase, followed by connectivity-mediated tau spreading in AD. Thus, attenuating amyloid-beta-related neuronal hyperactivity may limit p-tau release, tau aggregation and cognitive decline. To test this hypothesis, we will perform a translational research project combining clinical AD datasets with neuroimaging, fluid biomarkers, electrophysiology, and patient derived neuron cell models. With these translational data, we will assess mechanistic links between amyloid-beta, neuronal hyperactivity, p-tau increase and tau spreading across connected neurons/brain regions. Our findings will be essential to assess neuronal activity as a potential treatment target (e.g. by repurposing approved anti-epileptic drugs) to prevent tau spreading, neurodegeneration and cognitive decline. This work will be instrumental for informing future clinical trials targeting neuronal hyperexcitability for disease modification in AD.