胰岛素受体
胰岛素降解酶
转基因小鼠
IRS1
内分泌学
内科学
胰岛素
生物
淀粉样前体蛋白
淀粉样蛋白(真菌学)
神经退行性变
胰岛素抵抗
阿尔茨海默病
转基因
医学
生物化学
疾病
基因
植物
作者
Toshitaka Ochiai,Toshiharu Sano,Takeru Nagayama,Naoto Kubota,Takashi Kadowaki,Tomoko Wakabayashi,Takeshi Iwatsubo
标识
DOI:10.1016/j.nbd.2021.105510
摘要
Insulin signaling has been implicated in the metabolism as well as aging and longevity. Type 2 diabetes mellitus and its core pathology, insulin resistance, has also been implicated in the development of Alzheimer's disease (AD) and amyloid-β deposition in humans. By contrast, genetic ablation of the insulin/IGF-1 signaling (IIS) pathway components, e.g. insulin receptor substrate (IRS)-2, has been documented to suppress amyloid-β accumulation in the brains of transgenic mice overexpressing AD mutant β-amyloid precursor protein (APP). Therefore, the brain IIS may be a key modifiable molecular target in the pathophysiology of AD. IRS-1 and IRS-2 are critical nodes in IIS as substrates for insulin receptor and IGF-1 receptor, although the functional differences between IRS-1 and IRS-2 in the adult brain are yet to be explored. To examine their relative contribution to the brain IIS activity and AD pathomechanism, we generated APP transgenic mice lacking either IRS-1 or IRS-2. IRS-1 deficiency had little effects on the brain IIS pathway associated with compensatory activation of IRS-2, whereas IRS-2 deficiency was not fully compensated by activation of IRS-1, and the downstream activation of Akt also was significantly compromised. Pathological analyses of the cortical tissues showed that the biochemical levels of soluble and insoluble amyloid-β, the amyloid-β histopathology, and tau phosphorylation were not affected by the absence of IRS-1, in contrast to the marked alteration in IRS-2 deleted mice. These results suggest the predominance of IRS-2 in the brain IIS, and support the hypothesis that reduced IIS exerts anti-amyloid effects in the brain.
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