Tag Archives: Alzheimer’s disease

Nightmare on Wall Street

I’ve written several posts about Cassava Biosciences (symbol SAVA) and their potential drug for Alzheimer’s (see the end). The recent approval of Biogen’s ineffective (but highly lucrative) therapy Aducanumab for the disease brings forth the following nightmare. At a cost of > $50,000/year and millions of desperate famililes, Biogen will soon be rolling in money. The Cassava drug is orally available and should cost a fraction of that. Even better — it may actually work, although I think serious side effects are likely. Given the sketchy data getting Aducanumab through the FDA, Cassava’s drug represents a real threat to Biogen.

It will be perfectly legal for Biogen to outright buy Cassava and stop development. They will have the money. They won’t be able to do it on the sly, as any position of one company (or individual) in another greater than 5% of the value of the company must be reported to the SEC where it becomes public knowledge.

This from a cousin who is a stock market guru. His wife wasn’t available when I called being next door taking care of a woman with early Alzheimer’s, whose husband had to leave as his father suddenly passed away. She can’t be left alone. Such is the market for Aducanumab.

So will my friend Lindsay and her husband have the moral strength to resist Biogen?

Back in the day when I was in the service in Denver, a very wealthy stockbroker (who had brought the waterPik public) bought up many of beautiful old mansions on the west side of Cheeseman park. He then sold them to people he trusted (such as ourselves), so they wouldn’t be broken up into apartments (which was quite lucrative). I asked why the other people living on Humboldt street didn’t do the same. He said they had so much money they didn’t need character. The folks at Cassava don’t have a hell of a lot of money but hopefully they do have character.

Other posts on Cassava should you be interested are

The science behind Cassava Sciences (SAVA)

Do glia think? Take II

Do glia think Dr. Gonatas?  This was part of an exchange between G. Milton Shy, head of neurology at Penn, and Nick Gonatas a brilliant neuropathologist who worked with Shy as the two of them described new disease after new disease in the 60s ( myotubular (centronuclear) myopathy, nemaline myopathy, mitochondrial myopathy and oculopharyngeal muscular dystrophy).

Gonatas was claiming that a small glial tumor caused a marked behavioral disturbance, and Shy was demurring.  Just after I graduated, the Texas Tower shooting brought the question back up in force — https://en.wikipedia.org/wiki/University_of_Texas_tower_shooting.

Well that was 55 years ago, and we’ve learned a lot more about glia since.  

If glia don’t actually think, they may actually help neurons think better.  Since the brain is consuming 20% of your cardiac output as you sit there, it had better use the energy in the form of glucose  brought to it efficiently, and so it does, oxidizing it using oxygen (aerobic metabolism).  Glia on the other hand for reasons as yet unknown oxidize glucose anaerobically producing lactic acid (aerobic glycolysis). They transport the lactic acid to neurons and blocking transport impairs memory consolidation in experimental animals.  In fact aerobic glycolysis occurs in conditions of high synaptic plasticity and remodeling.  

The brain is 60% fat, some of which is cholesterol, which has to be made in the brain, as it doesn’t cross the blood brain barrier. Although neurons can synthesize cholesterol from scratch, most synthesis of cholesterol in the brain occurs in astrocytes.  It is than carried to neurons by apolipoprotein E.  As you are doubtless aware, apolipoprotein E (APOE) comes in three flavors 2, 3 and 4, and having two copies of APOE4 increases your risk of Alzheimer’s disease. 

But APOE does much more than schlep cholesterol to neurons according to a recent paper [ Neuron vol. 109 pp. 907 – 909, 957 – 970 ’21 ] Inside the particles are microRNAs.  You’ll recall that microRNAs decrease  the expression of proteins they target by binding to the messenger RNA (mRNA) for the targeted protein triggering its destruction. 

The microRNAs inside APOE suppress enzymes involved in de novo neuronal cholesterol biosynthesis (why work making cholesterol when the astrocyte is giving to you for free?).

This is unprecedented.  Passing metabolites (lactic acid, cholesterol) to neurons is one thing, but changing neuronal protein expression is quite another. 

Passing microRNAs in exosomes has been well worked out between cells (particularly cancer cells) outside the brain, but that’s for another time. 

The uses and abuses of Molarity

Quick what does a one Molar solution of a protein look like?

Answer: It doesn’t. The average protein mass is 100 kiloDaltons — http://book.bionumbers.org/how-big-is-the-average-protein/. That’s 100,000 grams per mole (100 kilograms).

A mole of any chemical is Avogadro’s number of it — or 6.02 x 10^23.  The molar mass counts 1 gram for each hydrogen it contains, 12 for each carbon etc. etc. 

A 1 molar concentration of any chemical is its molecular mass dissolved in 1 liter of water, which is 1,000 cubic centimeters (cc.).  The density of water is pretty much the same between 32 and 212 Fahrenheit (or 1 – 100 centigrade).  

What is the molar concentration of water, e.g. how many moles of water are in a liter of water.  The molecular mass of water is 18 so there are 1000/18 = 55.6 moles of water per liter of water.  

Well you can’t get 220 pounds of our 100 kiloDalton protein into 2.2 pounds (1 kiloGram) of water.  You could decorate each of the 6.02 x 10^23 protein molecules with 55 waters. 

Why belabor the obvious?  Because numbers are infinitely divisible and it is possible to talk about concentrations given in moles which make no chemical sense. Why?  Because matter is not infinitely divisible.  Divisibility for chemists stops at the atom level. 

Now let’s do some biology.  Cell size is measured in microns or 10^-6 meters.   A liter is a cube 10 centimeters on a side, so it is 10^-3 cubic meters.  A cubic micron is 10^-18 cubic meters, so there are 10^15 cubic microns in a liter. 

Now lets put 1 molecule in our cubic micron and each and every cubic micron in a liter of water.  What is its concentration in moles?  Our liter contains 10^15 molecules of our chemical, so its Molar concentration is 10^15/6.02 *10^23or .16 x 10^-8  or 1.6 x 10^-9 or 1.6 nanoMolar.    So 1 cubic micron is the volume  at which concentration less than 1.6 nanoMolar make no sense. 

It should be noted that 1 cubic micron contains plenty of water molecules to dissolve our molecule.  The actual number:

55 x 6.02 x 10^23/10^15 = 331 x 10^8  = 3 x 10^10 of them.

Notice that the mass of the molecule makes no difference.  Molar means moles/liter and liter is just a volume.  The number of molecules is what is crucial. 

As the volume goes up 1 molecule/volume makes sense at lower and lower concentrations. 

At this point the physicist says ‘consider a spherical cow’.  The biologist doesn’t have to.  We have lymphocytes which are nearly spherical with diameters ranging from 6 to 14 microns. 

Call it 10 microns.  Then the volume of our lymphocyte is  4/3 * pi * 5^3 = 524 cubic microns (call it 1,000 cubic microns to make things easier).  Recall that a liter contains 10^15 cubic microns.  So a liter can contain at most 10^12 lymphocytes, or 10^12 of our molecules so their concentration is 10^12/6.02 * 10^23 or 1.6 x 10^-12 molar. or 1.6 picoMolar.   Molar concentrations lower than 1.6 picoMolar make no chemical or biological sense in volumes of 1000 cubic microns. 

Are there chemicals in the lymphocyte with concentrations that low?  Sure there are.  Each chromosome is a molecule, so in male lymphocytes there is exactly one X chromosome and one Y. 

Next up.  Is a dissociation constant (Kd) in the femtoMolar (10^-15 Molar) range biologically meaningful?   I’m not sure and am still thinking about it, but the answer has some relevance to Alzheimer’s disease. 

Montana girl does good, real good !

Montana is flyover country. Nobody smart lives there. We all know that.

But when I got there in 1972 an issue of Science contained an article by State Legislator about a modification of general relativity — https://en.wikipedia.org/wiki/Kenneth_Nordtvedt.  MIT grad, Harvard Junior Fellow etc. etc. 

Then there was the son of a doc I practiced with in Billings.   Honors physics at Billings Senior high school placed him in 2nd year physics at Harvard, from which he graduated in 4 years obtaining a masters in physics as well. 

Then there was a local boy, the Thiokol engineer who predicted the Challenger disaster and was over-ruled. 

The great thing about Montana was that no one ever bragged about this sort of thing.  There were so few people, that no one felt compelled to tell you about themselves, you’d find out about them soon enough.  The classic example was an excellent surgeon and friend I practiced with for 15 years.  Only on reading his obituary last year did I find out that he had a Fulbright after college.

Which brings me to Lindsay, a girl I first met when she was a high school student.  The family were ranchers with a beautiful spread on the east face of the Crazy mountains north of Big Timber.  I’m not sure how we first met — I don’t think I saw any of them as a patient.  But we all became friends and the galactic premiere of a cello sonata I wrote with a 19 year old secretary in a lumberyard was in their living room. 

The two least important things about Lindsay are that she was a centerfold and an olympic silver medalist in woman’s two person crew.  Don’t get excited about the centerfold bit, she was fully clothed, but for some reason the Harvard Alumni magazine had a 2 page picture on a field of daisys of her back in the 80’s when she was there. 

Lindsay went on to get a PhD from Cambridge and her work and that of her husband may have come up with something useful for Alzheimer’s disease.  I’ll talk about the science behind it in a future post.  But when the news broke today, the stock of her company hit 70  (it was around 7 at the beginning of the year).  For details please see — https://finance.yahoo.com/m/49fa6153-4235-3866-bff2-5a35470e54da/why-cassava-sciences-stock.html.

Couldn’t happen to a nicer girl.  Of course it didn’t just happen.  Decades of hard work went into it.  So as you fly across the country, look down.  Some people down there might be even smarter than you are. 

Maybe the senile plaque really is a tombstone

“Thinking about pathologic changes in neurologic disease has been simplistic in the extreme.  Intially both senile plaques and neurofibrillary tangles were assumed to be causative for Alzheimer’s.  However there are 3 possible explanations for any microscopic change seen in any disease.  The first is that they are causative (the initial assumption).  The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer.  The third is they are tombstones, the final emanations of a dying cell.” I’ve thought this way for years, and the quote is from 2012: https://luysii.wordpress.com/2012/07/26/research-on-alzheimers-disease-the-bad-news-the-good-news/.

We now have some evidence that the senile plaque may be just a tombstone marking a dead neuron. Certainly attempts to remove the plaques haven’t helped patients despite billions spent in the attempt.

A recent paper [ Proc. Natl. Acad. Sci. vol. 117 pp. 28625–28631 ’20 –https://www.pnas.org/content/pnas/117/46/28625.full.pdf ] not only provides a new way to look at Alzheimer’s disease, but immediately suggests (to me at least) a way to test the idea. If the test proves correct, it will turn the focus of Alzheimer disease research on its ear.

Not to leave anyone behind, the senile plaque is largely made of a small fragment (the aBeta peptide 40 or 42 amino acids) from a much larger protein (the amyloid precursor protein [ APP ] — with well over 800 amino acids). Mutations in APP with the net effect of producing more aBeta are associated with familial Alzheimer’s disease, as are mutations in the enzymes chopping up APP to form Abeta (presenilin1, etc.).

The paper summarizes some evidence that the real culprit is neuronal uptake of the Abeta peptide either as a monomer, or a collection of monomers (an oligomer) or even the large aggregate of monomers seen under the microscope as the senile plaque.

The paper gives clear evidence that a 30 amino acid fragment of Abeta by itself without oligomerization can be taken up by neurons. Not only that but they found the protein on neuronal cell surface that Abeta binds to as well.

Ready to be shocked?

The protein taking Abeta into the neuron is the prion protein (PrPC) which can cause mad cow disease, wasting disease of elk and all sorts of horrible neurologic diseases among them Jakob Creutzfeldt disease.

Now to explain a bit of the jargon which follows. The amino acids making up our proteins come in two forms which are mirror images of each other. All our amino acids are of the L form, but the authors were able to synthesize the 42 amino acid Abeta peptide (Abeta42 below) using all L or all D amino acids.

It’s time to let the authors speak for themselves.

“In previous experiments we compared toxicity of L- and D-Aβ42. We found that, under conditions where L-Aβ42 reduced cell viability over 50%, D-Aβ42 was either nontoxic (PC12) or under 20% toxic . We later showed that L-Aβ is taken up approximately fivefold more efficiently than D-Aβ (28), suggesting that neuronal Aβ uptake and toxicity are linked.”

Well, if so, then the plaque is the tombstone of a neuron which took up too much Abeta.

Well how could you prove this? Any thoughts?

Cell models are nice, but animal models are probably better (although they’ve never resulted in useful therapy for stroke despite decades of trying).

Enter the 5xFAD mouse — it was engineered to have 3 mutations in APP known to cause Familial Alzheimer’s Disease + 2 more in Presenilin1 (which also cause FAD). The poor mouse starts getting Abeta deposition in its brain under two months of age (mice live about two years).

Now people aren’t really sure just what the prion protein (PrPC) actually does, and mice have been made without it (knockout mice). They are viable and fertile, and initially appear normal, but abnormalities appear as the mouse ages if you look hard enough. But still . . .

So what?

Now either knock out the PrPC gene in the 5xFAD mouse or mate the two different mouse strains.

The genes (APP, presenilin1 and PrPC) are on different chromosomes (#21, #14 and #20 respectively). So the first generation (F1) will have a normal counterpart of each of the 3 genes, along with a pathologic gene (e.g. they will be heterozygous for the 3 genes).

When members of F1 are bred with each other we’d expect some of them to have all mutant genes. If it were only 2 genes on two chromosomes, we’d expect 25% of he offspring (F2 generation) to have all abnormal genes. I’ll leave it for the mathematically inclined to figure out what the actual percentage of homozygous abnormal for all 3 would be).

What’s the point? Well, it’s easy to measure just what genes a mouse is carrying, so it’s time to look at mice with a full complement of 5xFAD genes and no PrPC.

If these mice don’t have any plaques in their brains, it’s game, set and match. Alzheimer research will shift from ways to remove the senile plaque, to ways to prevent it by inhibiting cellular uptake of the abeta peptide.

What could go wrong? Well, their could be other mechanisms and other proteins involved in getting Abeta into cells, but these could be attacked as well.

If the experiment shows what it might, this would be the best Thanksgiving present I could imagine.

So go to it. I’m an 80+ year old retired neurologist with no academic affiliation. I’d love to see someone try it.


Amyloid goes way back, and scientific writing about has had various zigs and zags starting with Virchow (1821 – 1902) who named it because he thought it was made out of sugar.  For a long time it was defined by the way it looks under the microscope being birefringent when stained with Congo red (which came out 100 years ago,  long before we knew much about protein structure (Pauling didn’t propose the alpha helix until 1951).

Birefringence itself is interesting.  Light moves at different speeds as it moves through materials — which is why your legs look funny when you stand in shallow water.  This is called the refractive index.   Birefringent materials have two different refractive indexes depending on the orientation (polarization) of the light looking at it.  So when amyloid present in fixed tissue on a slide, you see beautiful colors — for pictures and much more please see — https://onlinelibrary.wiley.com/doi/full/10.1111/iep.12330

So there has been a lot of confusion about what amyloid is and isn’t and even the exemplary Derek Lowe got it wrong in a recent post of his

“It needs to be noted that tau is not amyloid, and the TauRx’s drug has failed in the clinic in an Alzheimer’s trial.”

But Tau fibrils are amyloid, and prions are amyloid and the Lewy body is made of amyloid too, if you subscribe to the current definition of amyloid as something that shows a cross-beta pattern on Xray diffraction — https://www.researchgate.net/figure/Schematic-representation-of-the-cross-b-X-ray-diffraction-pattern-typically-produced-by_fig3_293484229.

Take about 500 dishes and stack them on top of each other and that’s the rough dimension of an amyloid fibril.  Each dish is made of a beta sheet.  Xray diffraction was used to characterize amyloid because no one could dissolve it, and study it by Xray crystallography.

Now that we have cryoEM, we’re learning much more.  I have , gone on and on about how miraculous it is that proteins have one or a few shapes — https://luysii.wordpress.com/2010/08/04/why-should-a-protein-have-just-one-shape-or-any-shape-for-that-matter/

So prion strains and the fact that alpha-synuclein amyloid aggregates produce different clinical disease despite having the same amino acid sequence was no surprise to me.

But it gets better.  The prion strains etc. etc may not be due to different structure but different decorations of the same structure by protein modifications.

The same is true for the different diseases that tau amyloid fibrils produce — never mind that they’ve been called neurofibrillary tangles and not amyloid, they have the same cross-beta structure.

A great paper [ Cell vol. 180 pp. 633 – 644 ’20 ] shows how different the tau protofilament from one disease (corticobasal degeneration) is from another (Alzheimer’s disease).  Figure three shows the side chain as it meanders around forming one ‘dish’ in the model above.  The meander is quite different in corticobasal degeneration (CBD) and Alzheimers.

It’s all the stuff tacked on. Tau is modified on its lysines (some 15% of all amino acids in the beta sheet forming part) by ubiquitination, acetylation and trimethylation, and by phosphorylation on serine.

Figure 3 is worth more of a look because it shows how different the post-translational modifications are of the same amino acid stretch of the tau protein in the Alzheimer’s and CBD.  Why has this not been seen before — because the amyloid was treated with pronase and other enzymes to get better pictures on cryoEM.  Isn’t that amazing.  Someone is probably looking to see if this explains prion strains.

The question arises — is the chain structure in space different because of the modifications, or are the modifications there because the chain structure in space is different.  This could go either way we have 500+ enzymes (protein kinases) putting phosphate on serine and/or threonine, each looking at a particular protein conformation around the two so they don’t phosphorylate everything — ditto for the enzymes that put ubiquitin on proteins.

Fascinating times.  Imagine something as simple as pronase hiding all this beautiful structure.



Barking up the wrong therapeutic tree in Alzheimer’s disease

Billions have been spent by big pharma (and lost) trying to get rid of the senile plaque of Alzheimer’s disease.  The assumption has always been that the plaque is the smoking gun killing neurons.  But it’s just an assumption which a recent paper has turned on its ear [ Proc. Natl. Acad. Sci. vol. 116 23040 – 23049 ’19 ]

It involves a protein, likely to be a new face even to Alzheimer’s cognoscenti.  The protein is called SERF1A (in man) and MOAG-4 in yeast. It enhances amyloid formation, the major component of the senile plaque.  SERF1A is clearly doing something important as it has changed little from the humble single yeast cell to man.

The major component of the senile plaque is the aBeta peptide of 40 and/or 42 amino acids.  It polymerizes to form the amyloid of the plaque.  The initial step of amyloid formation is the hardest, getting a bunch of Abeta peptides into the right conformation (e.g. the nucleus) so others can latch on to it and form the amyloid fiber.   It is likely that the monomers and oligomers of Abeta are what is killing neurons, not the plaques, otherwise why would natural selection/evolution keep SERF1A around?

So, billions of dollars later, getting rid of the senile plaque turns out to be a bad idea. What we want to do is increase SERF1A activity, to sop up the monomers and oligomers. It is a 180 degree shift in our thinking. That’s the executive summary, now for the fascinating chemistry involved.

First the structure of SERF1A — that is to say its amino acid sequence.  (For the nonChemists — proteins are linear string of amino acids, just as a word is a linear string of characters — the order is quite important — just as united and untied mean two very different things). There are only 68 amino acids in SERF1A of which 14 are lysine 9 are arginine 5 Glutamic acid and 5 Aspartic acid.  That’s interesting in itself, as we have 20 different amino acids, and if they occurred randomly you’d expect about 3 -4 of each.  The mathematicians among you should enjoy figuring out just how improbable this compared to random assortment. So just four amino acids account for 33 of the 68 in SERF1A  Even more interesting is the fact that all 4 are charged at body pH — lysine and arginine are positively charged because their nitrogen picks up protons, and glutamic and aspartic acid are negatively charged  giving up the proton.

This means that positive and negative can bind to each other (something energetically quite favorable).  How many ways are there for the 10 acids to bind to the 23 bases?  Just 23 x 22 x 21 X 20 X 19 X 18 x 17 x 16 x 15 x 14 or roughly 20^10 ways.  This means that SERF1A doesn’t have a single structure, but many of them.  It is basically a disordered protein.

The paper shows exactly this, that several conformations of SERF1 are seen in solution, and that it binds to Abeta forming a ‘fuzzy complex’, in which the number of Abetas and SERF1s are not fixed — e.g. there is no fixed stoichiometry — something chemists are going to have to learn to deal with — see — https://luysii.wordpress.com/2018/12/16/bye-bye-stoichiometry/.  Also different conformations of SERF1A are present in the fuzzy complex, explaining why it has such a peculiar amino acid composition.  Clever no?  Let’s hear it for the blind watchmaker or whatever you want to call it.

The paper shows that SERF1 increases the rate at which Abeta forms the nucleus of the amyloid fiber.  It does not help the fiber grow.  This means that the fiber is good and the monomers and oligomers are bad.  Not only that but SERF1 has exactly the same effect with alpha-synuclein, the main protein of the Lewy body of Parkinsonism.

So the paper represents a huge paradigm shift in our understanding of the cause of at least 2 bad neurological diseases.   Even more importantly, the paper suggests a completely new way to attack them.

Technology marches on — or does it?

Technology marches on — perhaps.  But it certainly did in the following Alzheimer’s research [ Neuron vol. 104 pp. 256 – 270 ’19 ] .  The work used (1) CRISPR (2) iPSCs (3) transcriptomics (4) translatomics to study Alzheimer’s.  Almost none of this would have been possible 10 years ago.

Presently over 200 mutations are known in (1) the amyloid precursor protein — APP (2) presenilin1 (3) presenilin2.  The presenilins are components of the gamma secretase complex which cleaves APP on the way to the way to the major components of the senile plaque, Abeta40 and Abeta42.

There’s a lot of nomenclature, so here’s a brief review.  The amyloid precursor protein (APP) comes in 3 isoforms containing 770, 751 and 695 amino acids.  APP is embedded in the plasma membrane with most of the amino acids extracellular.  The crucial enzyme for breaking APP down is gamma secretase, which cleaves APP inside the membrane.  Gamma secretase is made of 4 proteins, 2 of which are the presenilins.  Cleavage results in a small carboxy terminal fragment (which the paper calls beta-CTF) and a large amino terminal fragment. If beta secretase (another enzyme) cleaves the amino terminal fragment Abeta40 and Abeta42 are formed.  If alpha secretase (a third enzyme) cleaves the amino terminal fragment — Abeta42 is not formed.   Got all that?

Where do CRISPR and iPSCs come in?  iPSC stands for induced pluripotent stem cells, which can be made from cells in your skin (but not easily).  Subsequently adding the appropriate witches brew can cause them to differentiate into a variety of cells — cortical neurons in this case.

CRISPR was then used to introduce mutations characteristic of familial Alzheimer’s disease into either APP or presenilin1.  Some 16 cell lines each containing a different familial Alzheimer disease mutation were formed.

Then the iPSCs were differentiated into cortical neurons, and the mRNAs (transcriptomics) and proteins made from them (translatomics) were studied.

Certainly a technological tour de force.

What did they find?  Well for the APP and the presenilin1 mutations had effects on Abeta peptide production (but they differered).  Both however increased the accumulation of beta-CTF.  This could be ‘rescued’ by inhibition of beta-secretase — but unfortunately clinical trials have not shown beta-secretase inhibitors to be helpful.

What did increased beta-CTF actually do — there was enlargement of early endosomes in all the cell lines.   How this produces Alzheimer’s disease is anyone’s guess.

Also quite interesting, is the fact that translatomics and transcriptomics of all 16 cell lines showed ‘dysregulation’ of genes which have been associated with Alzheimer’s disease risk — these include APOE, CLU and SORL1.

Certainly a masterpiece of technological virtuosity.

So technology gives us bigger and better results

Or does it?

There was a very interesting paper on the effect of sleep on cerebrospinal fluid and blood flow in the brain [ Science vol. 366 pp. 372 – 373 ’19 ] It contained the following statement –”

During slow wave sleep, the cerebral blood flow is reduced by 25%, which lowers cerebral blood volume  by ~10%.  The reference for this statement was work done in 1991.

I thought this was a bit outre, so I wrote one of the authors.

Dr. X “Isn’t there something more current (and presumably more accurate) than reference #3 on cerebral blood flow in sleep?  If there isn’t, the work should be repeated”

I got the following back “The old studies are very precise, more precise than current studies.”

Go figure.

Will flickering light treat Alzheimer’s disease ? — Take II

30 months ago, a fascinating paper appeared in which flickering light improved a mouse model of Alzheimer’s disease.  The authors (MIT mostly) have continued to extend their work.   Here is a copy of the post back then.  Their new work is summarized after the ****

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/


The new work appears in two papers.

First [ Cell vol. 1777 pp. 256 – 271 ’19 ] 7 days of auditory tone stimuli at 40 cycles/second (40 Hertz) for just one hour a day reduced amyloid in the auditory cortex of the same pathetic mice described above (the 5XFAD mice).  They call this GENUS (Gamma ENtrainment Using sensory Stimuli).  Neurologists love to name frequencies in the EEG, and the 40 Hertz is in the gamma range.

The second paper [ Neuron vol. 102 pp. 929 – 943 ’19 ] is even better.  Alzheimer’s disease is characterized by two types of pathology — neurofibrillary tangles inside the remaining neurons and the senile plaque outside them.  The tangles are made of the tau protein, the plaques mostly of fragments of the amyloid precursor protein (APP).  The 5XFAD mouse had 3 separate mutations in the APP and two more in the enzyme that chops it up.

The present work looked at the other half of Alzheimer’s the neurofibrillary tangle.  They had mice with the P301S mutation in the tau protein found in a hereditary form of dementia (not Alzheimer’s) and also with excessive levels of CK-p25 which also results in tangles.

Again chronic visual GENUS worked in this (completely different) model of neurodegeneration.

This is very exciting stuff, but I’d love to see a different group of researchers reproduce it.  Also billions have been spent and lost on promising treatments of Alzheimer’s (all based on animal work).

Probably someone is trying it out on themselves or their spouse.  A EE friend notes that engineers have been trying homebrew transcranial magnetic and current stimulation using themselves or someone close as guineapigs for years.


The innate immune system is intrinsically fascinating, dealing with invaders long before antibodies or cytotoxic cells are on the scene.  It is even more fascinating to a chemist because it works in part by forming amyloid inside the cell.  And you thought amyloid was bad.

The system becomes even more fascinating because blocking one part of it (RIPK1) may be a way to treat a variety of neurologic diseases (ALS, MS,Alzheimer’s, Parkinsonism) whose treatment could be improved to put it mildly.

One way to deal with an invader which has made it inside the cell, is for the cell to purposely die.  More and more it appears that many forms of cell death are elaborately programmed (like taking down a stage set).

Necroptosis is one such, distinct from the better known and studied apoptosis.   It is programmed and occurs when a cytokine such as tumor necrosis factor binds to its receptor, or when an invader binds to members of the innate immune system (TLR3, TLR4).

The system is insanely complicated.  Here is a taste from a superb review — unfortunately probably behind a paywall — https://www.pnas.org/content/116/20/9714 — PNAS vol. 116 pp. 9714 – 9722 ’19.

“RIPK1 is a multidomain protein comprising an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The intermediate domain of RIPK1 contains an RHIM [receptor interacting protein (rip) homotypic interaction motif] domain which is important for interacting with other RHIM-containing proteins such as RIPK3, TRIF, and ZBP1. The C-terminal DD mediates its recruitment by interacting with other DD-containing proteins, such as TNFR1 and FADD, and its homodimerization to promote the activation of the N-terminal kinase domain. In the case of TNF-α signaling, ligand-induced TNFR1 trimerization leads to the assembly of a large receptor-bound signaling complex, termed Complex I, which includes multiple adaptors (TRADD, TRAF2, and RIPK1), and E3 ubiquitin ligases (cIAP1/2, LUBAC complex).”

Got that?  Here’s a bit more

“RIPK1 is regulated by multiple posttranslational modifications, but one of the most critical regulatory mechanisms is via ubiquitination. The E3 ubiquitin ligases cIAP1/2 are recruited into Complex I with the help of TRAF2 to mediate RIPK1 K63 ubiquitination. K63 ubiquitination of RIPK1 by cIAP1/2 promotes the recruitment and activation of TAK1 kinase through the polyubiquitin binding adaptors TAB2/TAB3. K63 ubiquitination also facilitates the recruitment of the LUBAC complex, which in turn performs M1- type ubiquitination of RIPK1 and TNFR1. M1 ubiquitination of Complex I is important for the recruitment of the trimeric IκB kinase complex (IKK) through a polyubuiquitin-binding adaptor subunit IKKγ/NEMO . The activation of RIPK1 is inhibited by direct phosphorylation by TAK1, IKKα/β, MK2, and TBK1. cIAP1 was also found to mediate K48 ubiquitination of RIPK1, inhibiting its catalytic activity and promoting degradation.”

So why should you plow through all this?  Because inhibiting RIPK1 reduces oxygen/glucose deprivation induced cell death in neurons, and reduced infarct size in experimental middle cerebral artery occlusion.

RIPK1 is elevated in MS brain, and inhibition of it helps an animal model (EAE).  Mutations in optineurin, and TBK1 leading to familial ALS promote the onset of RIPK1 necroptosis

Inflammation is seen in a variety of neurologic diseases (Alzheimer’s, MS) and RIPK1 is elevated in them.

Inhibitors of RIPK1 are available and do get into the brain.  As of now two RIPK1 inhibitors have made it through phase I human safety trials.

So it’s time to try RIPK1 inhibitors in these diseases.  It is an entirely new approach to them.  Even if it works only in one disease it would be worth it.

Now a dose of cynicism.  Diseased cells have to die one way or another.  RIPK1 may help this along, but it tells us nothing about what caused RIPK1 to become activated.  It may be a biomarker of a diseased cell.  The animal models are suggestive (as they always are) but few of them have panned out when applied to man.