Is sleep deprivation like Alzheimer’s and why we need sleep in the first place

Ask a cardiologist why the heart needs to pump and you’ll get a strange look. Ask any neuroscientist why the brain needs to sleep, and they’ll scratch their head — until now perhaps. A paper in Science a few days ago may have the answer [ Science vol. 342 pp. 316 – 317, 373 – 377 ’13 ] Essentially the brain gets washed out during sleep.

First — a bit of history. The tissue of the brain is so tightly packed that it is impossible to see the cells that make it up with the usual stains used by light microscopists. People saw nuclei all right but they thought the brain was a mass of tissue with nuclei embedded in it (like a slime mold). Muscle is like that — long fibers with hundreds of nuclei here and there. It wasn’t until that late 1800′s that Camillo Golgi developed a stain which would now and then outline a neuron with all its processes. Another anatomist (Ramon Santiago y Cajal) used Golgi’s technique and argued with Golgi that yes the brain was made of cells. Fascinating that Golgi, the man responsible for showing nerve cells, didn’t buy it. This was a very hot issue at the time, and the two received a joint Nobel prize in 1906 (only 5 years after the prizes began).

How tightly packed are the cells in the brain? The shortest wavelength of visible light is 4000 Angstroms. Cells in the brain are packed far more tightly. To see the space between the brain cell external membranes you need an electron microscope (EM). Just preparing a sample for EM really fries the tissue. Neurons are packed together with less than 1000 Angstroms between them. So how much of this is artifact of preparation for electron microscopy has never been clear to me. One study injected a series of quantum dots of known diameter into the cerebral spinal fluid (CSF) to see the smallest sized dot that could insinuate itself between neurons [ Proc. Natl. Acad. Sci. vol. 103 pp. 5567 – 5572 ’06 ]. The upper limit was around 350 Angstroms. No wonder the issue was contentious when all they had was light microscopy.

Surprisingly, the PNAS paper comes up with an estimate that brain extracellular space comprises 20% of brain volume. I find this hard to accept given the above. So how does the brain get rid of waste products? It turns out that there is a circulation of cerebrospinal fluid (CSF) of sorts. Inject a tracer that you can follow into the CSF. After a period of time the tracer enters the brain along arteries (not veins) and after still more time it leaves the brain along the veins (not the arteries). How the tracer gets to veins isn’t discussed in the Science papers. This has been called by the horrible name of the glymphatic system (don’t ask).

Using a great deal of ingenuity, experimental finesse and some very cooperative mice, the flow of CSF into, through and out of the brain was studied. Several findings are striking — the extracellular space (aka interstitial volume) dearly doubles (from 14% to 23%) during sleep. More importantly, the flow into the brain decreases by 95% when you wake the mouse up. Presumably flow out of the brain decreases by the same amount during wake. CSF flow into the brain was present only in the surface exposed to bulk CSF when the animals were awake.

So what? The Abeta peptide is held by many to be the culprit in Alzheimer’s disease. When injected into the mouse cerebral cortex (hardly a physiologic procedure) Abeta peptide is cleared twice as fast from the brain during sleep. We all know that you don’t think as well when sleep deprived, and this may be why. The current thinking on Alzheimer’s is that it isn’t the visible plaques that you can see under the microscope (made largely of Abeta peptide aggregates), but the soluble form of Abeta which you can’t see which causes the trouble. This always struck me as a cop out similar to the way docs would say that labyrinthitis was due to a virus (not that anyone every isolated one). You might as well say both are due to angels (or devils).

So the difficulty thinking with sleep deprivation may be similar to Alzheimer’s disease, if similar goings on occur in our brain. Distinguish this from the sleepiness due to sleep deprivation –Alzheimer patients often have disturbed sleep patterns, but they aren’t particularly sleepy when they’re awake.

The sleepiness may be due to the build up of something else. Bulk flow of fluid is incredibly nonspecific, and will carry anything soluble along with it. Adenosine has been mentioned as one metabolite building up which makes us sleepy. Probably looking for a single compound washed out by CSF as ‘the’ cause of sleepiness or cognitive problems, is like looking for ‘the’ single compound in kidney failure causing similar symptoms. It’s everything the kidney/brain filters and gets rid of.

So, at very long last, we may have found out why we spend 1/3 of our lives asleep.

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