Will flickering light treat Alzheimer’s disease ?

Big pharma has spent zillions trying to rid the brain of senile plaques, to no avail. A recent paper shows that light flickering at 40 cycles/second (40 Hertz) can do it — this is not a misprint [ Nature vol. 540 pp. 207 – 208, 230 – 235 ’16 ]. As most know the main component of the senile plaque of Alzheimer’s disease is a fragment (called the aBeta peptide) of the amyloid precursor protein (APP).

The most interesting part of the paper showed that just an hour or so of light flickering at 40 Hertz temporarily reduced the amount of Abeta peptide in visual cortex of aged mice. Nothing invasive about that.

Should we try this in people? How harmful could it be? Unfortunately the visual cortex is relatively unaffected in Alzheimer’s disease — the disease starts deep inside the head in the medial temporal lobe, particularly the hippocampus — the link shows just how deep it is -https://en.wikipedia.org/wiki/Hippocampus#/media/File:MRI_Location_Hippocampus_up..png

You might be able to do this through the squamous portion of the temporal bone which is just in front of and above the ear. It’s very thin, and ultrasound probes placed here can ‘see’ blood flowing in arteries in this region. Another way to do it might be a light source placed in the mouth.

The technical aspects of the paper are fascinating and will be described later.

First, what could go wrong?

The work shows that the flickering light activates the scavenger cells of the brain (microglia) and then eat the extracellular plaques. However that may not be a good thing as microglia could attack normal cells. In particular they are important in the remodeling of the dendritic tree (notably dendritic spines) that occurs during experience and learning.

Second, why wouldn’t it work? So much has been spent on trying to remove abeta, that serious doubt exists as to whether excessive extracellular Abeta causes Alzheimer’s and even if it does, would removing it be helpful.

Now for some fascinating detail on the paper (for the cognoscenti)

They used a mouse model of Alzheimer’s disease (the 5XFAD mouse). This poor creature has 3 different mutations associated with Alzheimer’s disease in the amyloid precursor protein (APP) — these are the Swedish (K670B), Florida (I716V) and London (V717I). If that wasn’t enough there are two Alzheimer associated mutations in one of the enzymes that processes the APP into Abeta (M146L, L286V) — using the single letter amino acid code –http://www.biochem.ucl.ac.uk/bsm/dbbrowser/c32/aacode.html.hy1. Then the whole mess is put under control of a promoter particularly active in mice (the Thy1 promoter). This results in high expression of the two mutant proteins.

So the poor mice get lots of senile plaques (particularly in the hippocampus) at an early age.

The first experiment was even more complicated, as a way was found to put channelrhodopsin into a set of hippocampal interneurons (this is optogenetics and hardly simple). Exposing the channel to light causes it to open the membrane to depolarize and the neuron to fire. Then fiberoptics were used to stimulate these neurons at 40 Hertz and the effects on the plaques were noted. Clearly a lot of work and the authors (and grad students) deserve our thanks.

Light at 8 Hertz did nothing to the plaques. I couldn’t find what other stimulation frequencies were used (assuming they were tried).

It would be wonderful if something so simple could help these people.

For other ideas about Alzheimer’s using physics rather than chemistry please see — https://luysii.wordpress.com/2014/11/30/could-alzheimers-disease-be-a-problem-in-physics-rather-than-chemistry/

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  • tangent  On December 14, 2016 at 6:47 am

    Hold on, why would shining light through the temporal bone have any reason to work? Those neurons don’t have photosensors installed. Electrical or electromagnetic induction of gamma frequency seems more relevant. I’m sure somebody is running 40 Hz rTMS and tACS right now.

    There is a certain amount of evidence of entrainment from binaural beat stimuli, if they want to come in by a different door.

    I do share or exceed your skepticism that this will affect actual Alzheimer’s, given what anti-amyloid drugs have already been tried.

  • luysii  On December 14, 2016 at 9:49 am

    Point well taken. There is something called photic epilepsy which triggered by intermittent light stimulation — a huge epidemic (over 700 cases) occurred in Japan due to a TV cartoon years ago. There was a lot in Europe when the refresh rate of TVs was 50 Hertz (it is faster now). Photic stimulation is routinely performed in EEGs and I have seen it provoke discharges (but luckily never a seizure as the technician stops the photic stimulation as soon as the EEG shows that a seizure is beginning.

  • DN  On December 14, 2016 at 9:42 pm

    I have wondered before if activity patterns underlie some brain diseases. For example, schizophrenia cases are discordant in about 50% of monozygotic twins raised together. Clearly the disorder can be caused by something other than genetics, viruses, contaminated foods, etc. Perhaps circulating waves of chemicals gets started (like the electrical loops of atrial fibrillation) and cause remodeling of the brain function (like the pathogenic remodeling of the heart in atrial fibrillation). Ditto for the cortical spreading depression of migraine.

    It might be possible that simple stimulators could cure devastating brain disease. Clever behavioral techniques might even help, in analogy to mirror therapy for phantom limb syndrome. I wonder if anyone has tried having paranoid schizophrenics stand in front of a mirror and imagine sending mind control rays to their own image.

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