Involvement of insulin receptor substrates in cognitive impairment and Alzheimer's disease
Daisuke Tanokashira
Wataru Fukuokaya
Akiko Taguchi
摘要：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 mefformin improves memory impairment.Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms in cluding 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.
机标关键词：
资助基金：a MEXTGrant-in-Aid for Scientific Research on Innovative Areas (brain environment)(JP24111536)a MEXTGrant-in-Aid for Scientific Research on Innovative Areas (to AT)JSPS KAKENHI(JP24650201)JSPS KAKENHI(JP26282026)JSPS KAKENHI(JP17K19951)JSPS KAKENHI(JP17H02188)JSPS KAKENHI(to AT)
论文发表日期：2019-01-01
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：5( 1330-1334 )
英文信息