Department of Neuroscience and Physiology, Neuroscience Institute, New York University Grossman School of Medicine, New York, USA.
Department of Pathology, New York University Grossman School of Medicine, New York, USA.
Alzheimers Dement. 2024 Nov;20(11):7954-7970. doi: 10.1002/alz.14273. Epub 2024 Oct 5.
It is unclear how early neuronal deficits occur in tauopathies, if these are associated with changes in neuronal network activity, and if they can be alleviated with therapies.
To address this, we performed in vivo two-photon Ca imaging in tauopathy mice at 6 versus 12 months, compared to controls, and treated the younger animals with a tau antibody.
Neuronal function was impaired at 6 months but did not deteriorate further at 12 months, presumably because cortical tau burden was comparable at these ages. At 6 months, neurons were mostly hypoactive, with enhanced neuronal synchrony, and had dysregulated responses to stimulus. Ex vivo, electrophysiology revealed altered synaptic transmission and enhanced excitability of motor cortical neurons, which likely explains the altered network activity. Acute tau antibody treatment reduced pathological tau and gliosis and partially restored neuronal function.
Tauopathies are associated with early neuronal deficits that can be attenuated with tau antibody therapy.
Neuronal hypofunction in awake and behaving mice in early stages of tauopathy. Altered network activity disrupted local circuitry engagement in tauopathy mice. Enhanced neuronal excitability and altered synaptic transmission in tauopathy mice. Tau antibody acutely reduced soluble phospho-tau and improved neuronal function.
在神经tau 病中，早期神经元缺陷是如何发生的，如果这些缺陷与神经元网络活动的变化有关，以及它们是否可以通过治疗来缓解，目前尚不清楚。
为了解决这个问题，我们在神经tau 病小鼠的 6 个月和 12 个月时进行了体内双光子 Ca 成像，与对照组进行了比较，并对年轻动物用 tau 抗体进行了治疗。
神经元功能在 6 个月时受损，但在 12 个月时没有进一步恶化，可能是因为在这些年龄皮质 tau 负担相当。在 6 个月时，神经元大多呈低活性，神经元同步性增强，对刺激的反应失调。在体外，电生理学显示出改变的突触传递和运动皮质神经元兴奋性增强，这可能解释了改变的网络活动。急性 tau 抗体治疗减少了病理性 tau 和神经胶质增生，并部分恢复了神经元功能。
神经tau 病与早期神经元缺陷有关，这些缺陷可以通过 tau 抗体治疗来减轻。
在神经tau 病的早期阶段，清醒和行为小鼠的神经元功能减退。改变的网络活动扰乱了神经tau 病小鼠的局部回路活动。tau 病小鼠的神经元兴奋性增强和突触传递改变。tau 抗体急性减少可溶性磷酸化 tau 并改善神经元功能。
