Del Pozo Aaron, Knox Kevin M, Lehmann Leanne M, Davidson Stephanie, Rho Seongheon Leo, Jayadev Suman, Barker-Haliski Melissa
Center for Epilepsy Drug Discovery (CEDD), Department of Pharmacy, University of Washington, Seattle, WA 98195, USA.
Department of Neurology, University of Washington, Seattle, WA 98195, USA.
Prog Neurobiol. 2024 Apr;235:102591. doi: 10.1016/j.pneurobio.2024.102591. Epub 2024 Mar 13.
Hyperexcitability is intimately linked to Alzheimer's disease (AD) pathology, but the precise timing and contributions of neuronal hyperexcitability to disease progression is unclear. Seizure induction in rodent AD models can uncover new therapeutic targets. Further, investigator-evoked seizures can directly establish how hyperexcitability and AD-associated risk factors influence neuropathological hallmarks and disease course at presymptomatic stages.
Corneal kindling is a well-characterized preclinical epilepsy model that allows for precise control of seizure history to pair to subsequent behavioral assessments. 2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control male and female mice were thus sham or corneal kindled for 2 weeks. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid β levels in hippocampus and prefrontal cortex were quantified.
APP/PS1 females were more susceptible to corneal kindling. However, regardless of sex, APP/PS1 mice experienced extensive seizure-induced mortality versus kindled Tg- controls. PSEN2-N141I mice were not negatively affected by corneal kindling. Mortality correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression versus controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice also exhibited soluble amyloid β upregulation and glial reactivity without plaque deposition.
Evoked convulsive seizures and neuronal hyperexcitability in pre-symptomatic APP/PS1 mice promoted premature mortality without pathological Aβ plaque deposition, whereas PSEN2-N141I mice were unaffected. Disruptions in serotonin pathway metabolism in APP/PS1 mice was associated with increased glial reactivity without Aβ plaque deposition, demonstrating that neuronal hyperexcitability in early AD causes pathological Aβ overexpression and worsens long-term outcomes through a serotonin-related mechanism.
神经元兴奋性过高与阿尔茨海默病（AD）病理密切相关，但神经元兴奋性过高对疾病进展的确切时间和作用尚不清楚。在啮齿动物AD模型中诱导癫痫发作可以发现新的治疗靶点。此外，研究者诱发的癫痫发作可以直接确定兴奋性过高和AD相关危险因素如何在症状前阶段影响神经病理学特征和疾病进程。
角膜点燃是一种特征明确的临床前癫痫模型，可精确控制癫痫发作史，以便与后续行为评估配对。因此，对2-3月龄的APP/PS1、PSEN2-N141I转基因对照雄性和雌性小鼠进行假手术或角膜点燃2周。对海马体和前额叶皮质中癫痫发作诱导的胶质细胞、血清素途径蛋白和淀粉样β水平的变化进行量化。
APP/PS1雌性小鼠更容易发生角膜点燃。然而，无论性别如何，与点燃的转基因对照小鼠相比，APP/PS1小鼠在癫痫发作后出现了广泛的死亡。PSEN2-N141I小鼠未受到角膜点燃的负面影响。死亡率与海马体中色氨酸羟化酶2和单胺氧化酶A蛋白表达相对于对照组的显著下调相关；在PSEN2-N141I小鼠中未检测到这些变化。点燃的APP/PS1小鼠还表现出可溶性淀粉样β上调和胶质细胞反应性，而无斑块沉积。
症状前APP/PS1小鼠诱发的惊厥性癫痫发作和神经元兴奋性过高促进了过早死亡，且无病理性Aβ斑块沉积，而PSEN2-N141I小鼠未受影响。APP/PS1小鼠血清素途径代谢的破坏与胶质细胞反应性增加相关，而无Aβ斑块沉积，表明早期AD中的神经元兴奋性过高通过血清素相关机制导致病理性Aβ过表达并恶化长期预后。
