he news media are reporting that researchers have cured Alzheimer's in mice by shining a
flickering light on them. Well, of course it's not that simple. Here's what is really
going on in that Nature paper by Iaccarino et al.
What theory were they testing?
The idea was that disrupted gamma oscillations have something to do with Alzheimer's.
It would make sense, because electrical oscillations in the brain depend on intact
neurons and neuronal connections, which are damaged in Alzheimer's disease.
What are gamma oscillations?
Gamma oscillations (or gamma waves) are the highest frequency of electrical
oscillations (around 40 Hz) in the brain. Some neurologists think they may be
related to attentive focus.
Are these ordinary mice?
No, mice can't get Alzheimer's disease. The researchers used genetically
mutated mice called 5XFAD mice. As the name suggests, they have five different
mutations. This is a very unrealistic model since no patient has more than one
mutation, but these mice make huge amounts of Abeta and get sick very quickly.
This makes it easier to find ways to protect against Abeta, which is a toxic
protein that scientists believe causes many of the symptoms of Alzheimer's.
How could a light cure Alzheimer's?
The light was used to induce gamma oscillations. First the researchers implanted
fiber optic cables in the hippocampus, which is the region
most strongly affected by Alzheimer's. Then they mutated the mice some more to
make their neurons respond to light. They did this by injecting a special virus
called AAV that contained a protein called channelrhodopsin2 fused to eYFP (yellow
fluorescent protein).
AAV is a benign, non-harmful virus that does not hurt the mice. When the virus replicated it filled the brain cells with light-sensitive proteins. The researchers sent a blue light from a laser through the fiber optic cables to activate these light-sensitive proteins, which caused the neurons to fire. This is called optogenetic stimulation. The laser was pulsed to stimulate the neurons at 40 Hz. They found a 53% decrease in Abeta (a.k.a. beta-amyloid or Aβ).
Then they repeated the experiment with ordinary mutant mice and an ordinary LED light source, set to flicker at 40 Hz, in their cage. This also worked, but only in the visual cortex, which is not much affected by AD.
Finally they showed that even in normal mice, which have almost no Abeta at all, with no virus and no fiber optic cable, and which cannot get Alzheimer's disease, a 40 Hz flickering LED light reduced the amount of Abeta in the visual cortex by the same amount as in the AD mice.
What does this mean?
It means that increasing the synchronized oscillations in the brain can reduce the
amount of Abeta. The microglia had gotten bigger and started engulfing the Abeta.
This means they shifted toward a phagocytic state.
What did it do to plaques?
It reduced plaques and soluble Abeta by the same amount. Scientists have known for
over two decades that plaques are harmless. But some researchers use plaques as a
proxy for the amount of Abeta, because they are easier to detect.
Why is the result important?
It means that neuronal activity may play a role in converting microglia to a
phagocytic state, which is one way the brain clears away Abeta.
We should keep in mind that hundreds of other things have also gotten rid of Abeta in transgenic mice. They are not a particularly good model for Alzheimer's because what works in these mice has very often not worked in people. There are also unresolved questions in the paper that scientists will need to understand, such as why the Abeta was reduced by half regardless of the initial amount of it. We should also keep in mind that the idea that Abeta causes Alzheimer's is still only a theory. We have no idea why Abeta is there, but we can be sure it's there for a reason.
What will it mean for patients?
Nobody is going to use light to treat Alzheimer's.
Please don't run out and buy a flickering light bulb. It will just give you a
headache. But there are many ways researchers could use the results to help patients.
- They will test patients to see if gamma oscillations are deficient in Alzheimer's. If so, it could be a way of diagnosing Alzheimer's. This is essential if we are going to find an effective treatment.
- If that pans out, they could implant stimulating electrodes in the brain of high risk patients, similar to the new experimental treatment for Parkinson's disease.
- They will check to see if there's such a thing as a lazy microglia. If so, they'll look for a way to prod them into working a little harder.
If all of the above pan out, they'll recommend everybody keeping their mind active. It might turn out that not using your brain makes you more susceptible to Alzheimer's. If so, then reading web pages about Alzheimer's disease could be the best way to prevent it.
Last edited dec 09 2016, 5:57 am
