40 Hz acoustic stimulation decreases amyloid beta and modulates brain rhythms in a mouse model of Alzheimer’s disease

Abstract

IntroductionThe accumulation of amyloid-beta (Aβ) is one of the neuropathologic hallmarks of Alzheimer’s disease (AD) and abnormal gamma band oscillations and brain connectivity have been observed. Recently, a therapeutic potential of gamma entrainment of the brain was reported by Iaccarino et al. However, the affected areas were limited to hippocampus and visual cortex. Therefore, we sought to test the effects of acoustic stimulation in a mouse model of AD.MethodsFreely moving 6-month-old 5XFAD mice with electroencephalogram (EEG) electrodes were treated with daily two-hour acoustic stimulation at 40Hz for 2 weeks. Aβ and microglia were evaluated by immunohistochemistry and ELISA. Evoked and spontaneous gamma power were analyzed by wavelet analysis. Coherence, phase locking value (PLV), and cross-frequency coupling were analyzed.ResultsThe number of Aβ plaques decreased in the pre-and infralimbic (PIL) and hippocampus regions and soluble Aβ-40 and Aβ-42 peptides in PIL in the acoustic stimulation group. We also found that the number of microglia increased in PIL and hippocampus. In EEG analysis, evoked gamma power was decreased and spontaneous gamma power was increased. Gamma coherence and phase locking value did not show significant changes. Cross-frequency coupling was shifted from gamma-delta to gamma-theta rhythm.ConclusionIn summary, we found that acoustic stimulation at 40Hz can reduce Aβ in the brain and restore the gamma band oscillations and the frontoparietal connectivity. Our data suggest that acoustic stimulation might alter the natural deterioration processes of AD and have a therapeutic potential in AD.

Multi-mechanical waves against Alzheimer’s disease pathology: a systematic review

“…In the study conducted by Martorell et al (2019), the trains of acoustic tones (1 h/day, 7 days period) evoked the clearance of Aβ soluble species and the decrease of Aβ plaques in the auditory cortex and hippocampus of 5xFAD and APP/PS1 mice; both mouse models exhibit marked Aβ plaque burden [ 30 ]. Similar results were found in another study [ 48 ] that used a longer stimulation protocol (2 h/day, 15 days period) and reported that 40-Hz AS stimulation decreased both soluble and insoluble Aβ species, accompanied by a reduction in Aβ plaque number throughout the brains of 5xFAD mice [ 48 ]. Interestingly, when AS was combined with another sensory modality (visual stimulation using light flickering at the same rate—40 Hz), a wider effect was produced across the brain, which exhibited reduced Aβ pathology not only in the auditory cortex and hippocampus but also in the medial prefrontal cortex of 5xFAD mice [ 30 ].…”

“…[ 65 ] X Auditory stimulation Lee et al . [ 48 ] X X X Martorell et al . [ 30 ] X X X X Clements-Cortes et al .…”

“…More recently, AS has been receiving increased attention due to its effectiveness in reducing Aβ and Tau pathology and improving cognitive abilities in AD animal models [ 30 , 48 ]. This is a sensory-based stimulation strategy delivered by trains of tones repeated at a specific frequency which has been associated with marked entrainment of brainwaves in the brains of AD transgenic mice [ 30 , 48 ] and AD patients [ 31 , 49 ]. In fact, Aβ and Tau pathologies are known to alter brain rhythmic oscillatory activities [ 50 ], mainly in high-frequency band waves, impacting the high-order cognitive domains [ 51 , 52 ].…”

“…The 40-Hz AS has been shown to modulate the immune response in the brains of AD transgenic mice with intense Aβ plaque burden, by increasing microglial activity [ 30 , 48 ] and astrocyte reactivity [ 30 ] (1 h/day, 7 days period [ 30 ]; 2 h/day, 14 days period [ 48 ]). However, the one-week-long AS study observed that the increase in microglial activation induced by AS was reversed one week after the end of the treatment [ 30 ].…”

“…However, the one-week-long AS study observed that the increase in microglial activation induced by AS was reversed one week after the end of the treatment [ 30 ]. Both studies have reported a decrease in soluble and insoluble Aβ species [ 30 , 48 ], possibly resulting from microglial activation. As the expression of inflammatory markers was not assessed, it was unknown if this increase in glial activation prompted or regulated neuroinflammation response.…”