How to treat Alzheimer’s disease

Let’s say you’re an engineer whose wife has early Alzheimer’s disease.  Would you build the following noninvasive device to remove her plaques?  [ Cell vol. 177 pp. 256 – 271 ’19 ] showed that it worked in mice.

Addendum 18 April — A reader requested a better way to get to the paper — Here is the title — “Multisensory Gamma Stimulation Ameliorates Alzheimer’s Associated Pathology and Improves Cognition”.  It is from MIT — here is the person to correspond to  —Correspondence — lhtsai@mit.edu

The device emits sound and light 40 times a second.  Exposing mice  to this 1 hour a day for a week decreased the number of senile plaques all over the brain (not just in the auditory and visual cortex) and improved their cognition as well.

With apologies to Steinbeck, mice are not men (particularly these mice which carry 5 different mutations which cause Alzheimer’s disease in man).  Animal cognition is not human cognition.  How well do you think Einstein would have done running a maze looking for food?

I had written about the authors’ earlier work and a copy of that post will be found after the ****.

What makes this work exciting is that plaque reduction was seen not only  in the visual cortex (which is pretty much unaffected in Alzheimer’s) but in the hippocampus (which is devastated) and the frontal lobes (also severely affected).  Interestingly, to be effective, both sound and light had to be given simultaneously

Here are the details about the stimuli  —

“Animals were presented with 10 s stimulation blocks interleaved with 10 s baseline periods. Stimulation blocks rotated between auditory-only or auditory and visual stimulation at 20 Hz, 40 Hz, 80 Hz, or with random stimulation (pulses were delivered with randomized inter-pulse intervals determined from a uniform distribution with an average interval of 25 ms). Stimuli blocks were interleaved to ensure the results observed were not due to changes over time in the neuronal response. 10 s long stimulus blocks were used to reduce the influence of onset effects, and to examine neural responses to prolonged rhythmic stimulation. All auditory pulses were 1 ms-long 10 kHz tones. All visual pulses were 50% duty cycle of the stimulation frequency (25 ms, 12.5 ms, or 6.25 ms in length). For combined stimulation, auditory and visual pulses were aligned to the onset of each pulse.”

The device should not require approval by the FDA unless a therapeutic claim is made, and it’s about as noninvasive as it could be.

What could go wrong?  Well a flickering light could trigger seizures in people subject to photic epilepsy (under 1/1,000).

Certainly Claude Shannon who died of Alzheimer’s disease, would have had one built, as would Fields medal winner Daniel Quillen had he not passed away 8 years ago.

Here is the post of 12/16 which has more detail

 

*****

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/