Effect Of 3-hydroxybutyrate Methyl Ester On Tau-pathology Pathway In Alzheimer’s Disease

Alzheimer’s disease(AD)is the most common neurodegenerative disease and has become the fourth leading cause of death for the elderly.The etiology of the disease is complex and the pathogenesis is not yet clear.At present,no drugs and methods for curing AD have been developed in the world.Hyperphosphorylation of tau protein is one of the most prominent pathological features of AD,which will subsequently lead to a series of other pathologies,such as neurofibrillary tangles,synaptic function damage and even neuronal death.3-Hydroxybutyrate(3HB)is one of the most important ketone bodies in the body.Its derivative,3-hydroxybutyrate methyl ester(HBME),can be obtained by esterification of 3HB in vitro.Due to its p H neutrality and amphiphilic nonpolarity of hydrophilic ester,it is easier to cross the blood-brain barrier,thus playing a role in the brain.Previous studies found that HBME can significantly improve the spatial learning and memory ability of AD model mice,prevent brain atrophy and inhibit the deposition of Aβ protein in the brain.On the molecular mechanism,on the one hand HBME can replace glucose to provide energy for the brain,on the other hand it can protect mitochondria and repair oxidative damage.However,the study did not involve whether HBME could act on tau pathological pathway at the same time.Therefore,this paper intends to further explore the intervention effect of HBME on tau pathological pathway.We used two phosphoenzyme inhibitors to treat mouse neuroblastoma-2a cell line to construct AD model cells,and carried out related studies.the results showed that HBME can enhance the expression level of synaptophysin 1 and PSD95,and improve the cell survival rate,which is mainly achieved by up-regulating the level of active phosphatase PP2A and inactive glycogen synthesis kinase GSK-3β,thus significantly inhibiting hyperphosphorylation of tau protein.Therefore,HBME can also improve AD by intervening the pathological pathway of tau protein,which enables us to have a deeper understanding of the mechanism of HBME on AD and provides a more comprehensive theoretical basis and experimental basis for its development into effective anti-AD drug.