Post by Deborah Joye
What's the science?
Alzheimer’s disease is a progressive form of dementia characterized by build-up of amyloid-beta (Aβ) protein plaques between nerve cells and tau protein ‘tangles’ inside of cells. Treatment options are limited, but promising research shows that neural activity can be manipulated to reduce Alzheimer’s pathology. Specifically, Alzheimer’s patients show a reduction in fast electrical ripples throughout the brain called gamma waves. Gamma waves can be induced non-invasively using a light programmed to flicker at a frequency of 40 Hz (gamma entrainment using sensory stimuli or GENUS). Exposure to the flickering light can produce gamma waves in the primary visual cortex, but it also reduces aggregates of Aβ protein, and activates microglia (the brain’s defense cells) to get rid of Aβ protein. But can GENUS be induced by other sensory systems? And can GENUS improve cognition in a model of Alzheimer’s disease? This week in Cell, Martorell and colleagues demonstrate that GENUS can be induced through both auditory and visual stimuli, reduce pathological Aβ and tau proteins, impact brain regions beyond primary sensory regions, and improve cognitive function in a mouse model of Alzheimer’s disease.
How did they do it?
The authors first checked to ensure that GENUS could be induced using an auditory tone by exposing mice to trains of tones repeating at various frequencies while simultaneously recording neural activity in the auditory cortex, hippocampus, and prefrontal cortex. To test whether auditory GENUS could improve recognition and spatial memory in a mouse model of Alzheimer’s disease, the authors employed several behavioral tasks that test hippocampus-dependent memory function: the novel object location and novel object recognition tests, which probe memory for identity or placement of an object, and the Morris Water Maze, which tests spatial memory for the location of a hidden platform. To investigate how GENUS might alter various Alzheimer’s-related proteins and cell-specific characteristics, the authors used immunohistochemistry to label Aβ and tau proteins, as well as other proteins involved with changes to astrocytes and microglia.
What did they find?
The authors found that exposure to a 40 Hz auditory tone induced GENUS in the auditory cortex, hippocampus, and prefrontal cortex. Critically, mice exposed to auditory GENUS performed better than control mice in three distinct hippocampal-dependent memory tasks, suggesting that GENUS can boost hippocampal function. Auditory GENUS also reduced the amount of Aβ protein and the pathological spreading of tau in the auditory cortex and hippocampus. Similar to effects of visual GENUS, auditory GENUS activated microglia, which increased in size and took up more Aβ. Finally, auditory GENUS increased the number of astrocytes, widened blood vessels, and increased a protein which helps to clear Aβ from the brain. When the two types of GENUS were combined, the authors found that microglia clustered around Aβ plaques, generally a precursor to phagocytosis and pathogen removal. Interestingly, auditory plus visual GENUS also reduced amyloid pathology throughout the neocortex, suggesting that inducing gamma oscillations with multiple sensory modalities can result in widespread reduction in Aβ throughout the brain.
What's the impact?
This study is the first to show that gamma waves can be induced in regions of the brain using trains of auditory tones. This study builds on previous work, demonstrating that GENUS can be induced using both auditory and visual stimuli. The authors show that auditory GENUS can improve hippocampus-dependent cognitive function in a mouse model of Alzheimer’s pathology, suggesting that GENUS could be used as a non-invasive treatment to improve cognition in Alzheimer’s patients. This research demonstrates that both auditory and visual GENUS can be used to decrease AD pathology, and that multi-sensory GENUS results in unique microglial responses to Aβ protein plaques that might increase their removal from the brain.
Martorell et al., Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition. Cell (2019). Access the original scientific publication here.