Université de Strasbourg, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364 CNRS, 12 Rue Goethe, Strasbourg, France.
ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), IMIS team, University of Strasbourg and CNRS, Strasbourg, France; CM2R (Research and Resources Memory Center), Geriatric Day Hospital, Neurogeriatric Service, Geriatrics Department, University Hospital of Strasbourg, Strasbourg, France.
Neurobiol Dis. 2024 Oct 15;201:106676. doi: 10.1016/j.nbd.2024.106676. Epub 2024 Sep 20.
Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease.
We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females).
Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions.
This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology.
路易体痴呆（DLB）是仅次于阿尔茨海默病的第二大常见与年龄相关的神经认知病理学。目前缺乏用于表征该疾病的动物模型，而开发这些模型将不仅有助于理解 DLB 的神经病理学机制，还将改善针对该疾病的临床前研究的效果。
我们对过表达野生型人α-突触核蛋白基因（mThy1-hSNCA，12 至 14 个月大的雄性）的转基因小鼠模型进行了广泛的表型特征描述。此外，我们还将我们的小鼠模型结果与包括 34 名健康对照和 55 名前驱期 DLB 患者（男性和女性）在内的患者队列中观察到的依赖于背海马（DH）和额皮质（FC）的神经心理学和神经病理学缺陷进行了比较。
我们的研究表明，mThy1-hSNCA 模型中可溶性α-突触核蛋白的病理性形式增加，主要在 FC 和 DH 中。然而，功能障碍以及炎症标志物的转录物增加和与可塑性相关的蛋白质水平降低仅发生在 FC 中。此外，我们在纹状体或黑质中未观察到病理生理学或酪氨酸羟化酶的改变，也未在我们的模型中观察到运动缺陷。有趣的是，来自前驱期 DLB 患者队列的结果也表明，FC 改变导致了功能缺陷，同时保留了通常与 DH 功能障碍相关的那些。
本研究表明，在 DLB 的早期阶段就观察到 FC 的病理生理学损伤伴随着 DH 的保留，并且 mThy1-hSNCA 小鼠模型与该病理学的一些标志物相似。
