Molecular Mechanisms in Neurodegenerative Dementia Laboratory, University of Montpellier, EPHE-PSL, INSERM U1198, Montpellier, France.
Department of Psychiatry and Neurosciences, Laval University, CR-CHU of Québec, Québec, Canada.
Epilepsia. 2022 Apr;63(4):919-935. doi: 10.1111/epi.17186. Epub 2022 Feb 28.
Although epilepsies and neurodegenerative disorders show pathophysiological similarities, their direct functional associations are unclear. Here, we tested the hypothesis that experimental seizures can induce tau hyperphosphorylation and amyloidogenic modifications over time, with intersections with neuroinflammation.
We used a model of mesial temporal lobe epilepsy (MTLE) where unilateral intrahippocampal injection of kainic acid (KA) in C57BL/6 mice elicits epileptogenesis and spontaneous focal seizures. We used a model of generalized status epilepticus (SE) obtained by intraperitoneal KA injection in C57BL/6 mice. We performed analyses and cross-comparisons according to a schedule of 72 h, 1 week, and 8 weeks after KA injection.
In experimental MTLE, we show AT100, PHF1, and CP13 tau hyperphosphorylation during epileptogenesis (72 h-1 week) and long-term (8 weeks) during spontaneous seizures in the ipsilateral hippocampi, the epileptogenic zone. These pathological modifications extended to the contralateral hippocampus, a seizure propagating zone with no histological lesion or sclerosis. Two kinases, Cdk5 and GSK3β, implicated in the pathological phosphorylation of tau, were activated. In this MTLE model, the induction of the amyloidogenic pathway (APP, C99, BACE1) was prominent and long-lasting in the epileptogenic zone. These Alzheimer's disease (AD)-relevant markers, established during seizure progression and recurrence, reciprocated an enduring glial (GFAP, Iba1) inflammation and the inadequate activation of the endogenous, anti-inflammatory, glucocorticoid receptor system. By contrast, a generalized SE episode provoked a predominantly transient induction of tau hyperphosphorylation and amyloidogenic markers in the hippocampus, along with resolving inflammation. Finally, we identified overlapping profiles of long-term hippocampal tau hyperphosphorylation by comparing MTLE to J20 mice, the latter a model relevant to AD.
MTLE and a generalized SE prompt persistent and varying tau hyperphosphorylation or amyloidogenic modifications in the hippocampus. In MTLE, an AD-relevant molecular trajectory intertwines with neuroinflammation, spatiotemporally involving epileptogenic and nonlesional seizure propagating zones.
尽管癫痫和神经退行性疾病具有相似的病理生理学表现，但它们之间的直接功能关联尚不清楚。在这里，我们检验了这样一个假设，即实验性癫痫发作可随时间诱导 tau 过度磷酸化和淀粉样蛋白形成修饰，并与神经炎症相交。
我们使用内侧颞叶癫痫（MTLE）模型，其中在 C57BL/6 小鼠的海马内单侧注射海人酸（KA）可引发癫痫发生和自发性局灶性癫痫发作。我们使用 C57BL/6 小鼠腹腔内注射 KA 获得的全面性癫痫持续状态（SE）模型。我们根据 KA 注射后 72 小时、1 周和 8 周的时间表进行分析和交叉比较。
在实验性 MTLE 中，我们在癫痫发生（72 小时-1 周）和自发性癫痫发作的长期（8 周）期间，在同侧海马（癫痫发作区）中观察到 AT100、PHF1 和 CP13 tau 过度磷酸化。这些病理修饰延伸到对侧海马，这是一个没有组织学损伤或硬化的癫痫传播区。两种激酶，Cdk5 和 GSK3β，参与 tau 的病理性磷酸化，被激活。在这种 MTLE 模型中，淀粉样蛋白形成途径（APP、C99、BACE1）的诱导在癫痫发作区非常明显且持久。这些与阿尔茨海默病（AD）相关的标志物在癫痫发作进展和复发期间建立，与持续的神经胶质（GFAP、Iba1）炎症和内源性抗炎性糖皮质激素受体系统的不适当激活相互作用。相比之下，全身性 SE 发作在海马中引起 tau 过度磷酸化和淀粉样蛋白形成标记物的主要短暂诱导，同时炎症消退。最后，我们通过将 MTLE 与 J20 小鼠进行比较，确定了长期海马 tau 过度磷酸化的重叠谱，后者是与 AD 相关的模型。
MTLE 和全身性 SE 会在海马中引起持续和不同的 tau 过度磷酸化或淀粉样蛋白形成修饰。在 MTLE 中，AD 相关的分子轨迹与神经炎症交织在一起，在时空上涉及癫痫发作区和非损伤性癫痫传播区。
