Abstract
BackgroundAlzheimer’s disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has 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.MethodsWe 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 Aβ levels 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.ResultsWe 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 Aβ plaques 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. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation.ConclusionThese results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity.
Highlights
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases that affects over 50 million people in the world
Aβ plaques are degraded by microglia and astrocytes [5] and soluble Aβ is removed through the perivascular pathway [6, 7]
Aβ loads in cortical and hippocampal regions changed after two weeks of transcranial ultrasound stimulation (tUS) at 40 Hz In the pre- and infra-limbic cortex (PIL), there was a significant decrease in total Aβ42 in the Tg/Stim+ group compared to the Tg/Stim- group
Summary
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases that affects over 50 million people in the world. Medications currently fail to prevent the aggregation of amyloid plaques in AD patients [8, 9], pharmacological and non-pharmacological treatments based on the amyloid hypothesis are still major goals in AD treatment research, especially those that aim at reducing the accumulated Aβ [10]. Neuronal activity with different frequencies of gammaband (~ 30 to 100 Hz) oscillation occurs across multiple brain regions, where it is assumed to play an important role in perception and cognitive functions such as attention, learning, and memory encoding and retrieval [11, 12]. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. 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
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