Establishment Of Neurodegenerative Disease Model Based On Monkeys And Exploration Of Non-invasive Physical Stimulation Therapy

After many years of research,the etiology and mechanism of Alzheimer’s disease(AD)are still unknown and incurable.Therefore,some scientists have proposed that it may be necessary to change the research ideas of AD treatment.So,people began to explore non-invasive physical therapy methods.This is a novel emerging strategy for the treatment of AD.In order to verify the results obtained by Tsai’s team of Massachusetts Institute of Technongy(MIT)from an AD mouse model using auditory stimulation,we chose aged rhesus monkeys with AD-related pathological changes as experimental animols of this study.To ensure the comparability of the experimental results,we used the same noninvasive physical stimulation(40 Hz auditory stimulation or random auditory stimulation)as MIT Tsai’s team on transgenic AD mice,and intervened in six aged rhesus monkeys(28-31 years old)to study the effects of auditory stimulation on the pathological markers of AD in the brain of aged rhesus monkeys.The results showed that the 40 Hz auditory stimulation significantly increased the concentrations of Aβ42 and Aβ40 in the cerebrospinal fluid(CSF)of aged rhesus monkeys.In addition,the impact of 40 Hz auditory stimulation on the Aβconcentration elevation was a long-lasting effect.According to previous studies,the concentration of Aβ in the CSF was inversely correlated with the Aβ load in brain.Therefore,our results are similar to the results of Lihui Tsai’s study on transgenic AD mice,indicating that 40 Hz auditory was able to significantly reduce at least some of the AD pathology in the brain of aged rhesus monkeys.The results obtained on aged rhesus monkeys provide further important support for our successful shift of auditory stimuli towards the treatment of AD in humans,and make us more confident to use the innovative therapy to further investigate the mechanism of AD and lay the foundation for the treatment and even cure of AD.The above is exploration of non-invasive physical stimulation therapy,and the next is establishment of neurodegenerative disease model based on monkeys.Whether direct manipulation of Parkinson’s disease(PD)risk genes in adult monkey brain can elicit Parkinsonian phenotype remains an unsolved issue.Here,we employed an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of the brain of two monkey groups: an old group(21 and 23 years old)and a middle age group(10 years old).After the operation,the old group exhibited all classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key PD pathologic hallmarks,such as severe nigral dopaminergic neuron loss(over64%)and obvious α-synuclein pathology in the gene edited SN.In contrast,the phenotypes of their middle age counterparts,which also showed clear PD symptoms and pathologic hallmarks,were less severe.In addition to the higher final total PD scores and more severe PD pathological changes,the old group also revealed higher vulnerability to gene editing by showing a faster PD progression in the process.Those results suggested that both the genetic and aging factors played important roles in the PD development of the monkeys.Together,this gene editing system can effectively develop a large quantity of genetically edited PD monkeys in a short time(6-10months),and thus,provides a practical transgenic monkey model for future PD studies.