Peters Samuel T, Fahrenkopf Allyssa, Choquette Jessica M, Vermilyea Scott C, Lee Michael K, Vossel Keith
Department of Neurology, N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN, United States.
Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States.
Front Neurol. 2020 Jun 19;11:563. doi: 10.3389/fneur.2020.00563. eCollection 2020.
Abnormal intraneuronal accumulation of the presynaptic protein α-synuclein (α-syn) is implicated in the etiology of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Recent work revealed that mice expressing human α-syn with the alanine-53-threonine (A53T) mutation have a similar phenotype to the human condition, exhibiting long-term potentiation deficits, learning and memory deficits, and inhibitory hippocampal remodeling, all of which were reversed by genetic ablation of microtubule-associated protein tau. Significantly, memory deficits were associated with histological signs of network hyperactivity/seizures. Electrophysiological abnormalities are often seen in parkinsonian dementias. Baseline electroencephalogram (EEG) slowing is used as a supportive diagnostic feature in DLB and PDD, and patients with these diseases may exhibit indicators of broad network dysfunction such as sleep dysregulation, myoclonus, and seizures. Given the translational significance, we examined whether human A53T α-syn expressing mice exhibit endogenous-tau-dependent EEG abnormalities, as measured with epidural electrodes over the frontal and parietal cortices. Using template-based waveform sorting, we determined that A53T mice have significantly high numbers of epileptiform events as early as 3-4 months of age and throughout life, and this effect is markedly attenuated in the absence of tau. Epileptic myoclonus occurred in half of A53T mice and was markedly reduced by tau ablation. In spectral analysis, tau ablation partially reduced EEG slowing in 6-7 month transgenic mice. We found abnormal sleeping patterns in transgenic mice that were more pronounced in older groups, but did not find evidence that this was influenced by tau genotype. Together, these data support the notion that tau facilitates A53T α-syn-induced hyperexcitability that both precedes and coincides with associated synaptic, cognitive, and behavioral effects. Tau also contributes to some aspects of EEG slowing in A53T mice. Importantly, our work supports tau-based approaches as an effective early intervention in α-synucleinopathies to treat aberrant network activity.
突触前蛋白α-突触核蛋白（α-syn）在神经元内的异常积聚与路易体痴呆（DLB）和帕金森病痴呆（PDD）的病因有关。最近的研究表明，表达丙氨酸-53-苏氨酸（A53T）突变的人α-syn的小鼠具有与人类疾病相似的表型，表现出长时程增强缺陷、学习和记忆缺陷以及海马抑制性重塑，而所有这些都通过微管相关蛋白tau的基因消融得到逆转。值得注意的是，记忆缺陷与网络活动亢进/癫痫发作的组织学迹象相关。帕金森病痴呆患者常出现电生理异常。基线脑电图（EEG）减慢被用作DLB和PDD的支持性诊断特征，这些疾病患者可能表现出广泛网络功能障碍的指标，如睡眠失调、肌阵挛和癫痫发作。鉴于其转化意义，我们研究了表达人A53T α-syn的小鼠是否表现出内源性tau依赖的EEG异常，通过额叶和顶叶皮质的硬膜外电极进行测量。使用基于模板的波形分类，我们确定A53T小鼠早在3 - 4个月大时以及整个生命过程中都有大量的癫痫样事件，并且在没有tau的情况下这种效应明显减弱。一半的A53T小鼠出现癫痫性肌阵挛，而tau消融使其明显减少。在频谱分析中，tau消融部分降低了6 - 7个月大的转基因小鼠的EEG减慢。我们发现转基因小鼠存在异常睡眠模式，在老年组中更为明显，但没有发现证据表明这受tau基因型影响。总之，这些数据支持这样的观点，即tau促进A53T α-syn诱导的过度兴奋，这种过度兴奋在相关的突触、认知和行为效应之前出现并与之同时发生。tau也导致A53T小鼠EEG减慢的某些方面。重要的是，我们的工作支持基于tau的方法作为α-突触核蛋白病的有效早期干预措施，以治疗异常的网络活动。
