Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological ...Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches.Impairment of gamma oscillations,which play an important role in perception and cognitive function,has been shown in mouse AD models and human patients.Recently,the therapeutic effect of gamma entrainment in AD mouse models has been reported.Given that ultrasound is an emerging neuromodulation modality,we investigated the effect of ultrasound stimulation pulsed at gamma frequency(40 Hz)in an AD mouse model.Methods:We implanted electroencephalogram(EEG)electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice(n=12 and 6,respectively).Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks,and the other six mice received sham treatment.Soluble and insoluble Aβlevels in the brain were measured by enzyme-linked immunosorbent assay.Spontaneous EEG gamma power was computed by wavelet analysis,and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.Results:We found that the total Aβ42 levels,especially insoluble Aβ42;in the treatment group decreased in pre-and infra-limbic cortex(PIL)compared to that of the sham treatment group.A reduction in the number of Aβplaques was also observed in the hippocampus.There was no increase in microbleeding in the transcranial ultrasound stimulation(tUS)group.In addition,the length and number of microglial processes decreased in PIL and hippocampus.Encel-phalographic spontaneous gamma power was increased,and cross-frequency coupling was normalized,implying functional improvement after tUS stimulation.Conclusion:These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβload and improving brain connectivity.展开更多
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(Ministry of Science and ICT,2016M3C7A1905475 and 2018R1A2B6006797 to JGK,2017R1A5A1014708 and 2018 R1A2B6002804 to TKMinistry of Education,2015R1D1A1A01059119 to TK)+1 种基金2021 Joint Research Project of Institutes of Science and Technology to TKKBRI basic research program through Korea Brain Research Institute funded by the Ministry of Science and ICT(21-BR-03-05)to JGK.
文摘Background:Alzheimer's disease(AD)is the most common cause of dementia,and is characterized by amyloid-β(Aβ)plaques and tauopathy.Reducing Aβhas been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches.Impairment of gamma oscillations,which play an important role in perception and cognitive function,has been shown in mouse AD models and human patients.Recently,the therapeutic effect of gamma entrainment in AD mouse models has been reported.Given that ultrasound is an emerging neuromodulation modality,we investigated the effect of ultrasound stimulation pulsed at gamma frequency(40 Hz)in an AD mouse model.Methods:We implanted electroencephalogram(EEG)electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice(n=12 and 6,respectively).Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks,and the other six mice received sham treatment.Soluble and insoluble Aβlevels in the brain were measured by enzyme-linked immunosorbent assay.Spontaneous EEG gamma power was computed by wavelet analysis,and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.Results:We found that the total Aβ42 levels,especially insoluble Aβ42;in the treatment group decreased in pre-and infra-limbic cortex(PIL)compared to that of the sham treatment group.A reduction in the number of Aβplaques was also observed in the hippocampus.There was no increase in microbleeding in the transcranial ultrasound stimulation(tUS)group.In addition,the length and number of microglial processes decreased in PIL and hippocampus.Encel-phalographic spontaneous gamma power was increased,and cross-frequency coupling was normalized,implying functional improvement after tUS stimulation.Conclusion:These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβload and improving brain connectivity.
