Mechanism Of BHBA Treatment On Improving Cognitive Function In 5XFAD Mice

As one of the characteristic pathological changes of Alzheimer's disease(AD),the main component of senile plaque(SP)is ?-amyloid(A?)peptide.A? is a normal metabolite in the body,which produced by modifying APP by cleavage enzyme,and its production and degradation are generally in dynamic equilibrium.When some factors cause abnormalities in APP metabolism,result in abnormal accumulation of A?.Studies have shown that a certain degree of abnormal deposition of A? would damage neurons,A? oligomers reduce the number of synapses,alter the transport of substances between neurons,induce oxidative stress,and impair mitochondrial function.Moreover,microglia activiated by A? can induce the synthesis and secretion of pro-inflammatory factors such as interleukin-1?(IL-1?),interleukin-6(IL-6)and tumor necrosis factor(TNF-?)after stimulation by A?,leading to neuronal damage and cognitive dysfunction ultimately.The above evidence indicates that weakening the neuronal loss,oxidative stress and inflammatory response caused by A? deposition,and reducing the production of A?,and promoting the degradation of A? can be used as a potential approach for the prevention and treatment of AD.Beta-hydroxybutyric acid(BHBA),an important component of ketone bodies in the blood,is an important endogenous metabolic intermediate produced by the metabolism of fatty acids and amino acids.It can supply energy to the brain through the blood-brain barrier,and almost replaces glucose into the brain during lactation.From this aspect it was called a main source of energy.BHBA is an endogenous ligand for G protein-coupled receptor 109A(GPR109A).Studies have shown that BHBA inhibits neuroinflammation through the GPAR109 A receptor and plays a neuroprotective role in the Parkinson's disease(PD)in vitro cell model.In addition,BHBA can improve mitochondrial respiration and promote ATP production against PD by mitochondrial respiratory through complex II-dependent manner,and BHBA derivative 3-hydroxybutyrate can counteract AD through mitochondrial protection mechanism.This indicates that BHBA can exert neuroprotective effects through various pathways.In our experiment,3.5-month-old ?-amyloid precursor protein(APP)and presenilin-1(PS1)double transgenic mice(5XFAD)were used as AD models,1.5 mmol / kg / d dose of BHBA subcutaneously.5XFAD mice were administered for 28 days.Morris water maze test,nesting experiment,passive avoidance experiment were used to evaluate the therapeutic effect of BHBA in preventing AD;and we observed the pathological changes of 5XFAD mice,including amyloid plaque deposition and microglia activation,to clarify whether BHBA threatment had the effects in SP deposition and neuroinflammation.In vitro,mouse hippocampal neurons(HT22 cells)were treated with 2 mmol BHBA to investigate the effects of BHBA on A? oligomer toxicity,ATP production,ROS production and mitochondrial aerobic respiration in hippocampal neurons.Changes in the expression levels of APP,beta-secretase(BACE1)and neprilysin(NEP),and the association between the expression of these enzymes and the GPR109 A receptor were examined under BHBA treatment.The results showed that BHBA treatment significantly improve the spatial learning ability,rises nesting score and fear memory in 5XFAD mice,which proved that BHBA can improves the cognitive function of 5XFAD mice.Then we found that BHBA attenuats A? accumulation and microglia overactivation,decreases the levels of A?1-40 and A?1-42 and the pro-inflammatory factors IL-1?,IL-6 and TNF-? gene expression levels,which suggest that BHBA exerts neuroprotective effects by reducing A? production and inflammation.Through vitro experiments,we found that BHBA can enhances mitochondrial respiratory function and protects hippocampal neurons from A? toxicity.Moreover,BHBA regulates the expression of APP and increases the expression of NEP by GPR109 A receptor.It is well documented that BHBA improves the cognitive function of 5XFAD mice through various mechanisms,and BHBA is promising as a drug candidate for AD prevention and treatment.