Menzies Institute For Medical Research, University of Tasmania, Hobart, Australia.
Wicking Dementia Research and Education Center, University of Tasmania, Hobart, Australia.
Mol Neurobiol. 2022 May;59(5):2962-2976. doi: 10.1007/s12035-022-02742-5. Epub 2022 Mar 6.
Amyotrophic lateral sclerosis (ALS) attacks the corticomotor system, with motor cortex function affected early in disease. Younger females have a lower relative risk of succumbing to ALS than males and older females, implicating a role for female sex hormones in disease progression. However, the mechanisms driving this dimorphic incidence are still largely unknown. We endeavoured to determine if estrogen mitigates disease progression and pathogenesis, focussing upon the dendritic spine as a site of action. Using two-photon live imaging we identify, in the prpTDP-43 mouse model of ALS, that dendritic spines in the male motor cortex have a reduced capacity for remodelling than their wild-type controls. In contrast, females show higher capacity for remodelling, with peak plasticity corresponding to highest estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomies and estrogen replacement with 17β estradiol in vivo was found to significantly alter spine density and mitigate disease severity. Collectively, these findings reveal that synpatic plasticity is reduced in ALS, which can be amelioriated with estrogen, in conjuction with improved disease outcomes.
肌萎缩侧索硬化症（ALS）侵袭皮质运动系统，运动皮层功能在疾病早期受到影响。与男性和老年女性相比，年轻女性患 ALS 的相对风险较低，这表明女性性激素在疾病进展中起作用。然而，导致这种二态性发病率的机制在很大程度上仍不清楚。我们试图确定雌激素是否能减轻疾病的进展和发病机制，重点关注树突棘作为作用部位。通过双光子活体成像，我们在 prpTDP-43 肌萎缩侧索硬化症小鼠模型中发现，雄性运动皮层中的树突棘的重塑能力低于其野生型对照。相比之下，女性表现出更高的重塑能力，其最大可塑性与发情周期中雌激素水平最高相对应。体内卵巢切除术和 17β 雌二醇雌激素替代的雌激素处理被发现显著改变了棘密度并减轻了疾病严重程度。总的来说，这些发现表明，ALS 中的突触可塑性降低，而雌激素可以与改善的疾病结果相结合来缓解这种情况。
