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expert reaction to restoring faulty brain waves reduces amyloid protein in mice

Publishing in Nature, scientists reported that exposing mice to specific frequencies of LED light reduced the level of amyloid protein, a protein associated with Alzheimer’s disease,  in the visual areas of the mouse brain.

 

Dr Frances Edwards, Reader in Neurophysiology, UCL, said:

“This is potentially a very interesting paper and if it is correct it is indeed a very important finding. Several people (including my group, Cummings et al., Brain 2015) have shown that there are very early changes in synaptic transmission even before amyloid plaques appear. The first effect of rising amyloid beta, when concentrations are very low, is a rise in the release of glutamate. If the brain cells are stimulated at 40 Hz this could greatly affect how the brain responds as the cell’s vesicles would be more likely to become depleted of this primary excitatory transmitter. So the idea suggested in this paper that the gamma rhythms and indeed other normal network function could be disturbed in early Alzheimer’s disease is certainly compatible with previous reports.

“Perhaps the most important study not mentioned in this paper is the work by Abramov et al (Nature Neuroscience, 2009) that shows in brain slices from normal wild-type rats (i.e. not transgenic ones) specific patterns of stimulation lead to the release of amyloid beta and, subsequently, a change in the likelihood of glutamate being release. Abramov et al suggest that in the healthy brain an optimal level of amyloid beta is needed to control transmitter release and that increasing or decreasing these levels would change network activity. Generally, however, in mice bred to display Alzheimer’s-like symptoms, I don’t think that it has been shown that using specific stimulus frequencies could decrease the release of amyloid beta and this seems to be clearly demonstrated here.

“I have a bit of a problem with some of the other data though. I thought it was particularly interesting that the authors reported a decrease in Amyloid beta 1-40 in the visual cortex of wild-type mice with 40Hz visual stimulation (Extended data Fig 6b), particularly as the levels of amyloid beta are so low in wild-type mice making detection very difficult even with the highly sensitive method used to test for the protein (ELISA). The concern comes from how throughout the paper all the data is normalised and in many cases clearly not normally distributed. This means the data should be tested with a special type of statistics called non-parametric statistics. The raw values are however available in the supplementary data and from a first analysis it is in some cases, particularly for the wild type mice, difficult to recreate the figure and analysis from the data given. Moreover for some of the visual flicker experiments, a rather unusual method of normalisation on their 7 day tests is described at the end of the data table, which may mean not all their data points are effectively independent. This could have a huge distortion of the effect. This distortion may mean that some results that at first seemed significant are actually not.

“However, on the plus side, a lot of the initial data using optogenetics is much tighter, clearly showing differences. Overall, if it is correct, then the possibility that changing the disturbed frequency of brainwave activity seen at early stages of Alzheimer’s disease to a more normal frequency will decrease Amyloid beta release is really interesting. This idea is certainly consistent with Abramov’s paper showing that amyloid beta release is very dependent on specific stimulus patterns – and perhaps in the future a therapy could even involve cognitively controlling frequencies for a period each day without having to use electrodes. As the authors themselves say, however, we must wait to see how this works in humans.

“For me I have some questions about the flicker data and the wild-type mouse information, but the optogenetic stimulation, assuming it doesn’t have similar problems affecting it, is really interesting, both in terms of Amyloid beta levels and the microglial data.

“The microglial gene expression also seems clear and consistent with the possible role of microglial proliferation and activation in controlling amyloid beta levels or its deposition. In a different line of APP/PS1 transgenic mice we have shown similar increases in expression of microglial genes that are very closely correlated with plaque load and suggest a possibly protective role for microglia which would be completely compatible with this (Matarin et al Cell Reports 10, 633–644).”

 

Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:

“This is an interesting scientific study using state of the art laboratory techniques. We already know that the electrical circuitry within the brain differs in people with Alzheimer’s disease.

“But what this study identifies is that a specific type of high frequency brainwave is reduced in animal models of Alzheimer’s disease before memory decline is detected. This disruption led to a double whammy in terms of the toxic amyloid beta peptide; on one hand it increased production and on the other decreased removal. To overcome this, the scientists used a genetic approach to selectively switch on nerve cells in response to light. This approach restored the high frequency brainwaves which reduced amyloid beta production, and interestingly altered other cells to promote amyloid beta removal.

“As the authors indicate we are some way off using this research as a rationale for new treatments. Importantly, we are still no clearer if this modulation of amyloid beta will provide cognitive benefits to patients.”

 

Dr Doug Brown, Director of Research, Alzheimer’s Society, said:

“This is certainly an interesting piece of work. While there are no immediate implications for people who are living with dementia, the study might well give us a spark for new avenues of research to further explore the relationship between rhythms of electrical activity in the brain and Alzheimer’s disease.

“The study suggests that restoring these rhythms in mice has an effect on deposits of amyloid in the brain – the toxic protein linked to the onset of Alzheimer’s. Unfortunately, it’s not completely clear what causes these rhythms to be disrupted in the first place or whether these findings will benefit people so further research is needed.”

 

Dr David Reynolds, Chief Scientific Officer, Alzheimer’s Research UK, said:

“This latest study in mice provides more evidence on the complex biology of Alzheimer’s and highlights the importance of changes in electrical rhythms in the disease. It is conceivable that changing brain cell rhythms could be a future target for therapies, but researchers will need to explore how light flickering approaches could not only reduce amyloid in the visual area of the brain but in those areas more commonly affected in Alzheimer’s.”

“Studies like this are valuable in revealing new processes implicated in Alzheimer’s disease and opening new avenues for further research. While mice used in this study showed some key features of Alzheimer’s, it is always important to follow up these findings in people. Researchers will now need to explore changes in these brain waves in people to explore their contribution to the disease and how any treatment approach could be practically and successfully implemented in people with Alzheimer’s disease.”

 

* ‘Gamma frequency entrainment attenuates amyloid load and modifies microglia’ by Iaccarino et al. will be published in Nature at 6pm UK time on Wednesday 7th December, which is also when the embargo will lift. 

 

Declared interests

Dr Edwards: “The mice we used in Matarin et al and in the first paper I mentioned were supplied by GSK.”

Dr Dallas:Receive funding from Alzheimer’s Research UK and The Alzheimer’s Association.”

Others – None received

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