ABSTRACT

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The deposition of amyloid plaques mainly composed of amyloid beta (Aβ) is observed in brain regions in AD patients. AD presents with similar pathophysiology to that of metabolic syndrome, including glucose and insulin resistance. In addition, epidemiological studies indicate diabetes, impaired glucose metabolism, and obesity increase the prevalence of AD. The liver is considered a key organ in the reciprocal relationship between AD and metabolic syndrome and is the major organ for the clearance of Aβ in the periphery. Furthermore, liver dysfunction aggravates Aβ-induced pathophysiology. Aβ is produced in the brain and peripheral tissues and penetrates the blood–brain barrier. However, in vivo evidence showing the effect of Aβ on the crosstalk between the brain and liver has not been reported yet. In the present study, we investigated the toxicity of brain-derived Aβ on glucose metabolism and the liver using transgenic mice overexpressing the carboxyl-terminal of amyloid precursor protein in the brain. The transgenic mice were overweight, which was associated with impaired glucose metabolism and insulin resistance, but not due to increased food intake. In addition, transgenic mice had enlarged livers and reduced gene expressions associated with glucose and lipid metabolism. Thus, overexpressed amyloid precursor protein in the brain may promote being overweight and glucose resistance, possibly through liver toxicity.

摘要

阿尔茨海默病 (AD) 是最普遍的神经退行性疾病。在 AD 患者的大脑区域观察到主要由淀粉样蛋白 β (Aβ) 组成的淀粉样斑块沉积。AD 表现出与代谢综合征相似的病理生理学，包括葡萄糖和胰岛素抵抗。此外，流行病学研究表明糖尿病、葡萄糖代谢受损和肥胖会增加 AD 的患病率。肝脏被认为是 AD 与代谢综合征相互关系中的关键器官，是清除外周 Aβ 的主要器官。此外，肝功能障碍加重了 Aβ 诱导的病理生理学。Aβ在大脑和外周组织中产生并穿透血脑屏障。然而，体内显示 Aβ 对大脑和肝脏之间串扰影响的证据尚未见报道。在本研究中，我们使用在大脑中过表达淀粉样前体蛋白羧基末端的转基因小鼠研究了脑源性 Aβ 对葡萄糖代谢和肝脏的毒性。转基因小鼠超重，这与葡萄糖代谢受损和胰岛素抵抗有关，但与食物摄入量增加无关。此外，转基因小鼠的肝脏增大，与葡萄糖和脂质代谢相关的基因表达减少。因此，大脑中过度表达的淀粉样蛋白前体蛋白可能通过肝毒性促进超重和葡萄糖抵抗。