Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China; Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, East Qingchun Road 3#, Hangzhou, Zhejiang 310016, China.
Neurobiol Aging. 2024 Mar;135:60-69. doi: 10.1016/j.neurobiolaging.2023.12.007. Epub 2023 Dec 31.
Alzheimer's disease (AD) is more prevalent in women than men, supposing due to the decline of estrogens in menopause, accompanied by increased gonadotropins such as luteinizing hormone (LH). We and others found that the transcription factor early growth response-1 (EGR1) regulates cholinergic function including the expression of acetylcholinesterase (AChE) and plays a significant role in cognitive decline of AD. Here we investigated in APP/PS1 mice by ovariectomy (OVX) and estradiol (E2) supplementation or inhibition of LH the effect on hippocampus-related cognition and related molecular changes. We found that OVX-associated cognitive impairment was accompanied by increased dorsal hippocampal EGR1 expression, which was rescued by downregulating peripheral LH rather than by supplementing E2. We also found in postmortem AD brains a higher expression of pituitary LH-mRNA and higher EGR1 expression in the posterior hippocampus. Both, in human and mice, there was a significant positive correlation between respectively posterior/dorsal hippocampal EGR1 and peripheral LH expression. We conclude that peripheral increased LH and increased posterior hippocampal EGR1 plays a significant role in AD pathology.
阿尔茨海默病（AD）在女性中比男性更为普遍，这可能是由于绝经后雌激素的下降，伴随着黄体生成素（LH）等促性腺激素的增加。我们和其他人发现，早期生长反应因子 1（EGR1）转录因子调节胆碱能功能，包括乙酰胆碱酯酶（AChE）的表达，并在 AD 的认知能力下降中起重要作用。在这里，我们通过卵巢切除术（OVX）和雌二醇（E2）补充或抑制 LH 研究了 APP/PS1 小鼠对海马相关认知和相关分子变化的影响。我们发现，OVX 相关的认知障碍伴随着背侧海马 EGR1 表达的增加，而通过下调外周 LH 而不是补充 E2 可以挽救这种增加。我们还发现，在 AD 患者的大脑中，垂体 LH-mRNA 和后海马的 EGR1 表达更高。在人和小鼠中，分别在后/背侧海马 EGR1 和外周 LH 表达之间存在显著的正相关。我们得出结论，外周 LH 的增加和后海马 EGR1 的增加在 AD 病理中起着重要作用。
