Exercise Delays The Progress Of Alzheimer’s Disease Through Activating Lysosomal Function

Aim:To study the effects of long-term running exercise training on lysosomal function in the brain of APP/PSEN1 transgenic mouse and explore whether exercise can delay the progression of Alzheimer’s disease by activating lysosomal function.Methods:Established the long-term exercise model of APP/PSEN1 mice by Rotary Fatigue Meter.The mice were trained on a treadmill from the 3 months old,40 min/day and 6 days/week for 7 months.Firstly,Lashley water maze and new object recognition experiments were used to evaluate the cognitive ability,and the the rotating rod and balance beam experiments were used to evaluate the motor coordination ability.The accumulation of P-amyloid peptide in the hippocampus of 10-month-old mice was observed by immunofluorescence,and the levels of Aβ,p-Tau(Ser396),APP,BACE andβ-CTF,the proteins that regulated the production of Aβ,were detected by Western blot.Then,the lysosomal morphology in neurons of CA1 region of hippocampal was observed by transmission electron microscopy.Additionally,Atg5,LC3,LAMP1,Cathepsin L and Cathepsin D were detected by Western blot.Subsequently,the regulating mechanism of exercise on lysosomal function in AD mice were analyzed,the colocalization of lysosomal and Aβ was then detected by immunofluorescence.The nuclear level of the TFEB was detected by nuclear isolation experiment and the transcription level of TFEB-regulated lysosome biogenesis associated genes were detected by qPCR.Furthermore,the effect of exercise on the mTOR pathway,the RIP1-ERK1/2 pathway and the calcineurin level,which may regulate the nuclear translocation of TFEB,were detected by Western blot.Finally,the effects of exercise on the maturation of lysosomal hydrolase were analyzed.The structure of Golgi was observed by electron microscopy and the levels of Golgi assembly protein GM130 and lysosomal hydrolase trfficking related proteins Rab7 and Rab9 were detected by immunoblotting.Results:Behavioral testing showed that long-term exercise significantly improved the cognitive and motor coordination in 9-month-old APP/PSEN1 mice.Exercise reduced Aβaccumulation through increasing the clearance of Aβ and affected little on the production of Aβ.In addition,electron microscopy results showed that exercise maintained the normal morphology of lysosomes in neurons of the CA1 region of hippocampal in AD.Exercise increased the level of Cathepsin L and Cathepsin D,maintained the normal level of LC3-II and p62 proteins,which suggested exercise enhancing autophagy-lysosome flux in the brain of AD mice.The colocalization of LAMP1 and Aβ also increased after exercise in AD mice.In the meanwhile,exercise promoted the nuclear translocation of TFEB and increased the transcription of genes associated with the lysosome biogenesis.Lastly,exercise maintained the normal structure and function of the Golgi complex and increased the level of the Rab7 and Rab9.All the data suggested that exercise enhanced the transportation and degradation of Aβ in lysosomes.Conclusion:Long-term exercise increases the clearance of Aβ by activating lysosomal function,thereby improving the cognitive ability of APP/PSEN1 mice and delaying the progress of Alzheimer’s disease.Lysosomes may become a new target for the treatment of some neurodegenerative diseases with mutant protein accumulation like Alzheimer’s disease.Long-term regular exercise may become a new treatment for Alzheimer’s disease.