Knox Kevin M, Beckman Megan, Smith Carole L, Jayadev Suman, Barker-Haliski Melissa
Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA 98195, United States of America.
Department of Neurology, School of Medicine, University of Washington, Seattle, WA 98195, United States of America.
Exp Neurol. 2023 Mar;361:114321. doi: 10.1016/j.expneurol.2023.114321. Epub 2023 Jan 9.
Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p < 0.02; females: p < 0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p = 0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p = 0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.
早发性阿尔茨海默病（EOAD）患者发生癫痫的风险升高，包括携带早老素2（PSEN2）变体的患者。与癫痫患者一样，未得到控制的癫痫发作可能会使AD患者的认知功能恶化。虽然癫痫发作与β-淀粉样蛋白积累之间的关系已得到更深入的研究，但EOAD中其他癫痫易感性驱动因素的作用仍相对未得到充分研究。因此，我们试图确定正常PSEN2功能丧失和慢性癫痫发作对老年大脑认知功能的影响。6月龄时，对雄性和雌性PSEN2基因敲除小鼠以及年龄和性别匹配的野生型（WT）小鼠进行假手术或角膜点燃。点燃和假点燃的小鼠在6周后接受一系列认知测试的挑战：非习惯化旷场试验（OF）、T迷宫自发交替试验（TM）和巴恩斯迷宫试验（BM），随后进行神经炎症和神经可塑性标志物的免疫组织化学检测。与WT小鼠相比，PSEN2基因敲除小鼠点燃所需的刺激明显更多（雄性：p < ０.０２；雌性：p < ０.０２）。在一系列行为测试中，与年龄匹配的WT雌性小鼠相比，点燃的雌性PSEN2基因敲除小鼠的认知表现受损最为明显。癫痫发作通常会使雄性小鼠的BM表现恶化（p = ０.０３８），但PSEN2功能丧失本身并不会使认知表现恶化。相反，点燃的PSEN2基因敲除雌性小鼠在BM试验中犯的错误最多（p = ０.００７）。慢性癫痫发作还以性别特异性方式显著改变了海马神经炎症和神经可塑性标志物的表达。因此，慢性癫痫发作可能会显著加重老年雌性而非雄性PSEN2基因敲除小鼠的海马依赖性认知缺陷。我们的研究表明，未经治疗的局灶性癫痫发作可能会以与性别相关的方式加重因正常PSEN2功能丧失而导致的认知负担。
