Study On The Pathology Of Senile Dementia And SUMO - 1 Modification

The characteristic pathological changes of Alzheimer’s disease (AD) include extracellular senile plaques formed by accumulated (3-amyloid proteins (AP), the neurofibrillar tangles formed by abnormal phosphorylated tau, neuronal dystrophy and neuronal loss, neurotransmitter system impairment and so on. In this experiment, we did some researches on exploring the relationship between pathological changes of Alzheimer’s disease (AD) and posttranslational modifier small ubiquitin related-modifier-1(sumo-1). The main research results are as follows:Part Ⅰ1. In SH-SY5Y cell model, western blot analysis showed that,A β promote SUMO1modification in the conditions of overexpression of SUMO-1. Aβ can promote UBA2, RANBP2and SENP1expression, inhibit UBC9expression; overexpression of SUMO-1can promote UBA2expression, inhibition RNBP2expression; SUMO-1overexpression can enhance the role of Aβ on UBA2, inhibited Aβ induced inhitition of UBC9causing an increase of UBC9expression. Overexpression of SUMO-1can inhibit the role of Aβ on the SENP1. These results indicate that Aβ may induce SUMO modification increased by SUMO modification system, depending on the expression level of SUMO-1espression..2. In the SH-SY5Y cell model, Aβ could induce the increase of ubiquitinated proteins with high molecular weight, implying the inhibition of proteasome by Aβ. Meanwhile, proteasome inhibition with an inhibitor MG132could significantly induce the increasing of ubiquitinated protein. However, the increase of SUMO-1decrorated protein was limited. Under the condition of SUMO-1overexpression, proteasome inhibition can facilitate SUMO-1modification; SUMO-1can promote MG132-induced increasing of ubiquitin modified proteins. In addition, SUMO-1can promote MG132-induced expressions of UBC9, UBA2, and inhibite the MG132-induced increasing of SENP1. These results indicated that the inhibition of proteasome could modulate SUMO-1decoration system, especially under SUMO-1overexpression.3. SUMO-1overexpression has no effect on MG132-induced ERK activation, but attanuated proteasome inhibitor MG132induced caspase-3、-6acyivation which are related to appoptosis. These results indicate that SUMO-1and ubiquitination can promote with each other.SUMO-1can inhibit apoptosis of proteasome inhibition, which indicates that SUMO-1has a protective effect.4. In the SH-SY5Y cell model, Western blot analysis showed that SUMO-1overexpresion promoted Aβ induced the increase of tau with higher molecular weight implying the increase of protein decorations. The inhibitors of phosphatase could promote SUMO-1modification, but the effect is not strong.Part II1. Compared with the12-month-old wild-type mice, Western blot assay showed that the SUMO-1expression and modification increased in the multiple brain regions of12months APPswe/PS1△the E9AD transfer gene mouse. Meanwhile, ubiquitin-modified protein as well as phosphorylated tau protein also increased in AD mice.2. Westernblot experiments showed APP protein and phosphorylated tau labeled by PS422antibody were no significant changed in the SUMO-1antibody immunoprecipitated protein of RIPA lysis buffer soluble protein fraction in from12months APPswe/PS1△E9transgenic AD mice compared with wildtype control mice. And tau5antibody labeled total tau protein is increased in the SUMO-1immunoprecipitated protein of soluble protein fraction in12months transgenic AD mice, but AT8labeled phosphorylated tau protein is decreased in the SUMO-1immunoprecipitates.3. Double immunofluorescent labeling showed that SUMO-1could be distributed in amyloid plaques, there are some partially co-localization of SUMO-1with AT8labeled phosphorylated tau in plaques in brain of APPswe/PS1△E9mice. Considering the decrease of SUMO-1decorated phosphorylated tau protein in soluble protein fraction from AD mice, we supposed that SUMO-1decorated phosphorylated tau protein might be in an insoluble condition, which implied SUMO-1taking a role in chronic neurodegeneration.In conclusion, SUMO-1overexpression could modulate Aβ induced changes of sumolyation and de-sumolyation related enzymes, causing the increase of SUMO-1or ubiquitin decorated proteins. Aβ induced change of SUMO-1decoration is related to the effects of Aβ on proteasome inhibition. SUMO-loverexpession might promote protein deposition and tau aggregation which is related to chronic neuronal degeneration. However, SUMO-1is protective for acute apoptosis in that its inhibitive effects on caspase-3,6.