Hearing loss is associated with an increased risk of Alzheimer disease (AD). However, the mechanisms of hearing loss promoting the onset of AD are poorly understood. Here we show that hearing loss aggravates cognitive impairment in both wild-type mice and mouse models of AD. Embryonic growth/differentiation factor 1 (GDF1) is downregulated in the hippocampus of deaf mice. Knockdown of GDF1 mimics the detrimental effect of hearing loss on cognition, while overexpression of GDF1 in the hippocampus attenuates the cognitive impairment induced by deafness. Strikingly, overexpression of GDF1 also attenuates cognitive impairment in APP/PS1 transgenic mice. GDF1 activates Akt, which phosphorylates asparagine endopeptidase and inhibits asparagine endopeptidase-induced synaptic degeneration and amyloid-β production. The expression of GDF1 is downregulated by the transcription factor CCAAT-enhancer binding protein-β. These findings indicate that hearing loss could promote AD pathological changes by inhibiting the GDF1 signaling pathway; thus, GDF1 may represent a therapeutic target for AD.

帕金森病(Parkinson's disease,PD)是临床最常见的神经系统退行性疾病之一,多见于中老年人,随着全球老龄化的加剧,PD发病率日渐增高,当前全球 PD患者超过 600 万人[1],预计到 2040 年将超过 1200 万[2],PD 影响患者运动、认知、精神和睡眠等多项功能,对社会和患者家庭造成极大的负担.PD的特征性病理改变为黑质致密部多巴胺能神经元的进行性丢失和残留神经元内路易小体的形成[3].

The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson’s disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson’s disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson’s disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson’s disease.

目的建立α-突触核蛋白(α-synuclein,α-syn)聚集及传播的细胞和动物模型,为帕金森病的发病机制研究提供基础.方法亲和层析法纯化α-syn蛋白,体外诱导其聚集成为α-syn纤维(Preformed fibrils,PFFs);培养稳定表达GFP-α-syn的HEK293细胞系及原代神经元,转导α-synPFFs后免疫荧光染色法观察细胞内cα-syn聚集情况;小鼠立体定位注射α-syn PFFs,免疫组织化学法检测内源性α-syn的聚集及传播情况.结果纯化的α-syn可在体外聚集形成聚集体;在细胞及动物水平观察到α-syn PFFs可诱导内源性蛋白的聚集和传播.结论本研究建立了 α-syn聚集及传播的细胞和动物模型,为帕金森病的相关研究打下了基础.