Research Of The SH2B1 Protein Interacting With Aβ And Their Mechanisms In AD Drosophila Model

Alzheimer’s disease（AD）is a neurodegenerative disease,with typical clinical symptoms including loss of memory and personality change,characterized by extracellular senile plaques,neurofibrillary tangles and neuronal cell death and progressive neurodegenerative.In AD,extracellular plaque mainly includes amyloid beta peptide（Aβ）,Aβas a risk factor plays an important role in the pathogenesis of AD.In AD patients,we found that the increase of age,positive family history of diabetes,virus infection,illiteracy and low education,low economic level,depression are all risk factors.Vascular dementia is at risk of a series of cerebral vascular factors（ischemic and hemorrhagic,acute or chronic hypoxic cerebrovascular disease,etc.）lead to brain damage caused by a group of clinical syndrome characterized by cognitive decline.We found in the literature and clinical practice that patients with,hypertension,hyperlipidemia,diabetes,heart disease high homocysteine are all high risk factors for the onset of vascular dementia.Among these two kinds of dementia,diabetes is the inter risk factors.We respectively to study about the mechanism of increased risk of dementia of diabetic patients from the molecular biological and clinical aspects.In AD model of fruit flies,insulin is identified as a neural pathways involved in learning and memory modulator,and is also closely related with Aβmetabolism and toxicity.SH2B1 protein is a key point in insulin signaling pathways involved in regulating insulin receptor activity.We have found in fruit flies giant fiber pathways（giant fiber system,GF）neurons,the expression of Aβ₄₂ in these neurons causes Aβaccumulation and age dependent synaptic dysfunction,motor ability recession and the phenomenon of neural degeneration leading to premature death.We respectively observed in Aβ₄₂ flies that loss of SH2B1 protein and excessive expression of neurons in Aβ₄₂ accumulation and its influence in neural degenerative diseases.To this end,we use[Gal4]A307 flies（specific to the expression of transcription factor Gal4 in GF pathways）uas-Aβ₄₂ and uas-SH2B flies(under the drive of transcription factor Gal4 respectively expressed Aβ₄₂ and SH2B1 protein)and SH2B1 gene knock down flies(as the heterozygous SH2B^-/+)Neurotransmitter of fruit flies GF pathways,climbing capacity,life span,Aβ₄₂ accumulation in neurons were tested.We found that in AD model of fruit flies partically knockout the SH2B1 is harmful to drosophila behavi,ability and neurotransmitter.By ELISA and immune dyeing method,we found that knockout SH2B1 increases the accumulation of Aβ₄₂ in neurons,in addition,the overexpression of SH2B1 improve fruit fly behavior ability and neurotransmitter and accumulation of Aβ₄₂ in neurons.Therefore,SH2B1 is likely to be Aβ₄₂ metabolic upstream modulator,role in the pathogenesis of AD to curb Aβ₄₂ accumulation.Therefore SH2B1 could be the potential targets for the treatment of the common dementia.We use MMSE and MoCA and found that diabetes is a potential high risk factors of early cognitive dysfunction of vascular dementia.