title: SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42. Partial knockout of neuronal SH2B in the Aβ42-expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42, as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42-expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42. Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia.
authors: Department of Neurology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Yijun
authors: Y
authors: Shen
authors: Department of Neurology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Yiling
authors: Y
authors: Xia
authors: Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Shiquan
authors: S
authors: Meng
authors: Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.|Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Nastasia K H
authors: NK
authors: Lim
authors: Department of Neurology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.|Department of Neurology, Xin Hua Hospital Chongming Branch Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Wenan
authors: W
authors: Wang
authors: Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Fude
authors: F
authors: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D029721:Drosophila Proteins; D007328:Insulin; D010446:Peptide Fragments; C518910:SH2B1 protein, human; C075222:amyloid beta-protein (1-42); D051058:Oncogene Protein v-akt
keywords: Alzheimer’s disease; SH2B1 protein; amyloid-β accumulation; diabetes