Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease

被引:21
作者
Ochiai, Toshitaka [1 ,2 ]
Sano, Toshiharu [1 ]
Nagayama, Takeru [1 ]
Kubota, Naoto [3 ,4 ]
Kadowaki, Takashi [3 ,5 ]
Wakabayashi, Tomoko [1 ,6 ]
Iwatsubo, Takeshi [1 ]
机构
[1] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Tokyo, Japan
[2] Kaken Pharmaceut Co LTD, Drug Res Ctr, Pharmacol Dept, Kyoto, Japan
[3] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo, Japan
[4] Univ Tokyo, Dept Clin Nutr Therapy, Tokyo, Japan
[5] Toranomon Gen Hosp, Tokyo, Japan
[6] Univ Tokyo, Grad Sch Med, Dept Innovat Dementia Prevent, Tokyo, Japan
关键词
Amyloid-beta; Neurodegenerative disease; Tau protein; Insulin; Insulin receptor substrate; Akt; Insulin signaling; Alzheimer's disease; LIFE-SPAN; A-BETA; NUTRIENT HOMEOSTASIS; DIABETES-MELLITUS; ADULT NEURONS; MICE LACKING; RESISTANCE; GROWTH; DISRUPTION; PHOSPHORYLATION;
D O I
10.1016/j.nbd.2021.105510
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
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-beta 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-beta accumulation in the brains of transgenic mice overexpressing AD mutant beta-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-beta, the amyloid-beta 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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页数:11
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