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Jan032017

Non-invasive gamma oscillations show promise for reducing amyloid plaque

It is well established that Alzheimer’s disease (AD) is a fatal neurodegenerative disorder, which currently afflicts ~5.4 million Americans1. There are five FDA drugs approved to treat the debilitating symptoms of AD1, but no therapeutic to date can alleviate the underlying pathology. Recently, solanezumab, an experimental AD drug developed by Eli Lilly, failed to significantly slow the progression of cognitive decline in a phase 3 clinical trial2. Failure of this AD drug, and many others, is complicated by both the heterogeneity of AD and the extensive anatomical damage caused by the disease. A common hypothesis is that by the time AD symptoms emerge, neurological injury is beyond repair. To circumvent these issues, ideal AD treatments would be non-toxic, non-invasive, and prophylactic.
A recent report from Iaccarino and Singer et al. identified a non-invasive light-based intervention to reduce Aβ plaque formation (a hallmark of AD pathology) in AD mouse models3. This study established a link between gamma waves (a particular type of neural oscillation) and AD-related neurotoxicity. First, the authors determined that gamma waves were reduced in the hippocampus of pre-symptomatic AD mice (5XFAD model) as compared to wild-type controls, through electrophysiological recordings. To better understand the function of gamma waves, mice were engineered using optogenetics to produce 40 hertz (Hz) gamma oscillations upon pulses of light in a specific region of the brain (fast-spiking parvalbumin interneurons). One hour of gamma wave production was sufficient to reduce Aβ protein levels by ~40% as determined by enzyme-linked immunosorbent assays (ELISA) and immunohistochemistry (IHC). Next, authors investigated gene expression profiles altered by gamma wave production through RNA sequencing. Interestingly, genes associated with the engulfing state of microglia (immune cells of the brain) were enriched. As determined by IHC, microglia were enlarged and co-localized with Aβ plaques, suggesting that gamma waves stimulated microglial-mediated phagocytosis of Aβ.
To further the application of these findings, the authors engineered a 40 Hz light flickering paradigm to stimulate gamma waves in the mouse visual cortex non-invasively. Analogous to the optogenetic approach, one hour of light flicker intervention reduced Aβ protein levels in the visual cortex of AD and wild-type mice by 20-58%, as determined by ELISA. These effects were acute (lasting less than twenty-four hours) and constrained to the visual cortex (Aβ protein was not reduced in the hippocampus). In AD mice, the light flicker intervention also resulted in enlarged microglia that engulfed Aβ protein, as determined by IHC and fluorescence-activated cell sorting combined with ELISA. Finally, the authors investigated whether the light flicker intervention had utility in mice with advanced Aβ plaque formation. One hour of light flicker intervention for seven consecutive days resulted in reduction of Aβ plaque by ~67% and also reduced Tau phosphorylation (another hallmark of AD pathology).
Taken together this extensive mechanistic study provides a promising foundation for non-invasive AD treatment. Moving forward it will be important to explore the long-term effects of 40 Hz light flickering on plaque load, brain atrophy, cognition, and survival time. Future studies combining transcranial magnetic stimulation to produce 40 Hz gamma oscillations and amyloid positron emission tomography imaging in humans could further determine the in vivo relationship between gamma waves and Aβ plaque formation in AD patients.
-TMG
1) Alzheimer’s Association, http://www.alz.org/research/overview.asp, 3 November 2016.
2) New York Times, “Eli Lilly’s Experimental Alzheimer’s Drug Fails in Large Trial”,  http://www.nytimes.com/2016/11/23/health/eli-lillys-experimental-alzheimers-drug-failed-in-large-trial.html?_r=0, 3 November 2016. 
3) Iaccarino and Singer et al. (2016) Gamma frequency entrainment attenuates amyloid load and modifies microglia Nature. 

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