Inflammatory Responsive Hydrogel For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease（AD）is a progressive neurodegenerative disease with insidious onset.In 2009,the number of AD cases registered worldwide reached 35.6 million,and it is estimated that this number will double by 2050.Studies have shown that the accumulation of amyloid fibers formed by the aggregation of amyloid beta proteins（A beta）in nervous tissues is one of the important factors causing Alzheimer’s disease.Chronic inflammation in the brain also plays an important role in the occurrence and development of AD.AD and related types of dementia are still incurable.Current treatment methods can only achieve moderate relief of symptoms,with high side effects,and can not be fundamentally cured.Studies have shown that hyaluronic acid（HA）is degraded in a large amount in brain microenvironment,and the downregulation of Neuregulin1（NRG1）expression is closely related to the development of AD.Nude mole（Heterocephalus glaber,NMRS）is the longestlived rodent.The high expression of HMW-HA and NRG1 in its brain microenvironment makes it able to tolerate high levels of Aβ_1-42 aggregation and resist Aβ_1-42 neurotoxicity,thus antagonizing the appearance of ADrelated phenotypes,and even plaque formation is not seen in the 29 years old model.In this study,the HAS2 gene of nude mole was cloned into HEK293 cell line,and stable HEK293-nmrHAS2 cell line secreting HMW-HA of nude mole was obtained.The product identification of HMW-HA proved that the nude mole HMW-HA had been obtained.To prevent the degradation of HMW-HA,the HMW-HA was modified by sulfhydrylation and PE.In order to respond to ADinduced brain inflammation,an inflammationresponsive hydrogel triglycerol monostearates（TM）,which can be decomposed by esterase and highexpression matrix metalloproteinase（MMPs）,was selected in this study.The modified HMW-HA and NRG1 were encapsulated into TM hydrogel network to form TM-HA-NRG1 inflammation response hydrogel.The TM-HA-NRG1 hydrogel was characterized and the concentration of each component was optimized to simulate the brain microenvironment of nude mole.TM-HA-NRG1hydrogel was cultured in the supernatant of esterase,matrix metalloproteinase and activated microglia culture respectively.TM-HA-NRG1 hydrogel showed that it could release different amounts of HMW-HA and NRG1 according to the intensity of inflammation environment.When TM-HA-NRG1 hydrogel was cocultured with activated microglia,the expressions of inflammatory related factors NO,IL-1β,IL-6,TNF-αand iNOS were significantly downregulated.In microglial environment,TM-HA-NRG1 hydrogel was cocultured with neurons.Under the stimulation of A beta oligomer,TM-HA-NRG1 hydrogel had significant protective effect on neurons in inflammatory environment and antagonized apoptosis induced by inflammation.In this study,we used the antiAD mechanism of nude mole mice to simulate the brain microenvironment of nude mole mice and construct an inflammationresponsive hydrogel,which provided a new idea and method for the treatment of AD.