Two seemingly unrelated recent papers could turn our attention away from chemistry and toward physics as the basic problem in Alzheimer’s disease. God knows we could use better therapy for Alzheimer’s disease than we have now. Any new way of looking at Alzheimer’s, no matter how bizarre,should be welcome. The approaches via the aBeta peptide, and the enzymes producing it just haven’t worked, and they’ve really been tried — hard.
The first paper [ Proc. Natl. Acad. Sci. vol. 111 pp. 16124 – 16129 ’14 ] made surfaces with arbitrary degrees of roughness, using the microfabrication technology for making computer chips. We’re talking roughness that’s almost smooth — bumps ranging from 320 Angstroms to 800. Surfaces could be made quite regular (as in a diffraction grating) or irregular. Scanning electron microscopic pictures were given of the various degrees of roughness.
Then they plated cultured primitive neuronal cells (PC12 cells) on surfaces of varying degrees of roughness. The optimal roughness for PC12 to act more like neurons was an Rq of 320 Angstroms.. Interestingly, this degree of roughness is identical to that found on healthy astrocytes (assuming that culturing them or getting them out of the brain doesn’t radically change them). Hippocampal neurons in contact with astrocytes of this degree of roughness also began extending neurites. It’s important to note that the roughness was made with something neurons and astrocytes never see — silica colloids of varying sizes and shapes.
Now is when it gets interesting. The plaques of Alzheimer’s disease have surface roughness of around 800 Angstroms. Roughness of the artificial surface of this degree was toxic to hippocampal neurons (lower degrees of roughness were not). Normal brain has a roughness with a median at 340 Angstroms.
So in some way neurons and astrocytes can sense the amount of roughness in surfaces they are in contact with. How do they do this — chemically it comes down to Piezo1 ion channels, a story in themselves [ Science vol. 330 pp. 55 – 60 ’10 ] These are membrane proteins with between 24 and 36 transmembrane segments. Then they form tetramers with a huge molecular mass (1.2 megaDaltons) and 120 or more transmembrane segments. They are huge (2,100 – 4,700 amino acids). They can sense mechanical stress, and are used by endothelial cells to sense how fast blood is flowing (or not flowing) past them. Expression of these genes in mechanically insensitive cells makes them sensitive to mechanical stimuli.
The paper is somewhat ambiguous on whether expressing piezo1 is a function of neuronal health or sickness. The last paragraph appears to have it both ways.
So as we leave paper #1, we note that that neurons can sense the physical characteristics of their environment, even when it’s something as un-natural as a silica colloid. Inhibiting Piezo1 activity by a spider venom toxin (GsMTx4) destroys this ability. The right degree of roughness is healthy for neurons, the wrong degree kills them. Clearly the work should be repeated with other colloids of a different chemical composition.
The next paper [ Science vol. 342 pp. 301, 316 – 317, 373 – 377 ’13 ] Talks about the plumbing system of the brain, which is far more active than I’d ever imaged. The glymphatic system is a network of microscopic fluid filled channels. Cerebrospinal fluid (CSF) bathes the brain. It flows into the substance of the brain (the parenchyma) along arteries, and the fluid between the cellular elements (interstitial fluid) it exchanges with flows out of the brain along the draining veins.
This work was able to measure the amount of flow through the lymphatics by injected tracer into the CSF and/or the brain parenchyma. The important point about this is that during sleep these channels expand by 60%, and beta amyloid is cleared twice as quickly. Arousal of a sleeping mouse decreases the influx of tracer by 95%. So this amazing paper finally comes up with an explanation of why we spend 1/3 of our lives asleep — to flush toxins from the brain.
If you wish to read (a lot) more about this system — see an older post from when this paper first came out — http://luysii.wordpress.com/2013/10/21/is-sleep-deprivation-like-alzheimers-and-why-we-need-sleep-in-the-first-place/
So what is the implication of these two papers for Alzheimer’s disease?
The surface roughness of the plaques (800 Angstroms roughness) may physically hurt neurons. The plaques are much larger or Alzheimer would never have seen them with the light microscopy at his disposal.
The size of the plaques themselves may gum up the brain’s plumbing system.
The tracer work should certainly be repeated with mouse models of Alzheimer’s, far removed from human pathology though they may be.
I find this extremely appealing because it gives us a new way of thinking about this terrible disorder. In addition it might explain why cognitive decline almost invariably accompanies aging, and why Alzheimer’s disease is a disorder of the elderly.
Next, assume this is true? What would be the therapy? Getting rid of the senile plaques in and of itself might be therapeutic. It is nearly impossible for me to imagine a way that this could be done without harming the surrounding brain.
Before we all get too excited it should be noted that the correlation between senile plaque burden and cognitive function is far from perfect. Some people have a lot of plaque (there are ways to detect them antemortem) and normal cognitive function. The work also leaves out the second pathologic change seen in Alzheimer’s disease, the neurofibrillary tangle which is intracellular, not extracellular. I suppose if it caused the parts of the cell containing them to swell, it too could gum up the plumbing.
As far as I can tell, putting the two papers together conceptually might even be original. Prasad Shastri, the author of the first paper, was very helpful discussing some points about his paper by Email, but had not heard of the second and is looking at it this weekend.