Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease  

作　　者：Daisuke Tanokashira Wataru Fukuokaya Akiko Taguchi 

机构地区：[1]Department of Integrative Aging Neuroscience, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan [2]Division of Neurology, Endocrinology, and Metabolism, Faculty of Medicine University of Miyazaki, Miyazaki, Japan

出　　处：《Neural Regeneration Research》2019年第8期1330-1334,共5页中国神经再生研究（英文版）

基　　金：supported by a MEXTGrant-in-Aid for Scientific Research on Innovative Areas(brain environment)(JP24111536; to AT);JSPS KAKENHI(JP24650201,JP26282026,JP17K19951,JP17H02188; to AT);grants from the Mitsubishi Foundation(to AT);NOVARTIS Foundation Japan for the Promotion of Science(to AT)

摘　　要：Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid p accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS 1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS 1 /1 RS2-mediated signaling in the central nervous system and cognitive decline.Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1(IGF1) signaling(IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease(AD). The insulin receptor substrate(IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

关 键 词：type 2 diabetes insulin/insulin^like growth factor-1 INSULIN receptor substrate Alzheimer's disease aging SERINE phosphorylation METFORMIN NEUROPROTECTIVE effects high-fat-diet 

分 类 号：R[医药卫生]