GDF1 ameliorates cognitive impairment induced by hearing loss.
Lina PanChunrui LiLanxia MengGuoxin ZhangLi ZouYe TianSen ChenYu SunDandan SuXingyu ZhangMin XiongTingting XiaoDanhao XiaZhengyuan HongZhentao ZhangPublished in: Nature aging (2024)
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.
Keyphrases
- hearing loss
- cognitive impairment
- transcription factor
- signaling pathway
- binding protein
- wild type
- cell proliferation
- mouse model
- mild cognitive impairment
- poor prognosis
- epithelial mesenchymal transition
- metabolic syndrome
- high fat diet induced
- multiple sclerosis
- skeletal muscle
- prefrontal cortex
- subarachnoid hemorrhage
- insulin resistance
- stress induced