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. 

Another way to study Alzheimer’s

Until I read the paper PLOS Genet. 14, e1007791 (2018)., I thought that this was a sure way to win Nobel prize.  It’s still pretty interesting.  The abstract in Science was misleading, implying that there was an APOE4 variant which was actually protective against Alzheimer’s disease. That would have been fantastic, as it would provide a clue as to just what the APOE4 allele was doing to increase the risk of Alzheimer’s disease.

A huge amount of work has been done on APOE4.   Googling produced 433,000 results (0.46 seconds).  Theories abound but we still don’t know.

The authors studied Blacks and Puerto Ricans and found that if you inherited the APOE4 allele from an African source (rather than a European source), your chance of developing Alzheimer’s disease was significantly less.  A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study.

The numbers: ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background).

Note that the ORs are still up for Alzheimer’s if you have APOE4, but the differences are significant and certainly real given the size of the study.

The authors think it’s the area around the APOE  gene, rather than the total genetic background (African vs. European etc. etc.)

It still might be worth doing the following.  Take skin fibroblasts from all four types of people (Puerto Ricans with APOE4 on African background, Puerto Ricans with APOE4 on European background, Blacks with APOE4 on African background, APOE4 on a European background).

Make induced pluripotent stem cells (iPSCs) from them (the technology to do so is quite advanced). Differentiate these iPSCs into neurons  and others into glia (technology quite available).  Study protein and mRNA expression, epigenetic modifications in neurons and glia from all 4 groups.  This might tell you just what APOE4 was doing in high and lower risk people, and possibly might give a clue as to how it was increasing Alzheimer’s risk.

My hopes were really up, because the abstract in Science implied that APOE4 in Blacks and Puerto Ricans was actually absolutely rather than relatively protective, which would have given us some serious clues to Alzheimer pathogenesis, when APOE4 protective cells were contrasted with APOE4 increased risk cells.

Oh well.

The most interesting thing to an evolutionist is not that APOE4 increases the risk of Alzheimer’s disease

Neurologists were immensely excited by the discovery 25 years ago that the APOE4 variant of APOlipoprotein E increases the risk of Late Onset Alzheimer’s Disease (LOAD). 24,000 papers later (Google Scholar) we still don’t know how it does it. Should all this work have been done ? Of course ! !  Once we know the mechanism(s) by which APOE4 increases Alzheimer’s risk we’ll have new ideas to help us attack.

The APOE gene has 3 variants (alleles) APOE2, 3 and 4. The protein is average sized (299 amino acids). The 3 alleles differ at two positions (amino acids #112 and #158) where either cysteine or arginine can be found. The frequency of APOE4 is 14% in the adult white population, that of E3 is 78% and that of E2 is 8%.

Fascinating as this all is, it’s not what’s interesting from an evolutionary point of view.

[ Proc. Natl. Acad. Sci. vol. 113 pp. 17 – 18, 74 – 79 ’16 ] Postmenpausal longevity in females is not limited to humans. Humans, orcas and pilot whales are the only vertebrate species known to have prolonged postreproductive lifespans. Our fertility ends at about the same age that fertility ends in other female hominids (the great apes). However, apes rarely live into their 40s (even in captivity).

Unlike APOE4, APOE2 and APOE3 protect against late onset Alzheimer’s.

The fascinating point is that APOE2 and APOE3 aren’t found in the great apes. They are a human invention. Now LOAD occurs well past reproduction, so there should be no reason in terms of reproductive success for them to arise and be more common in human populations than the original APOE4.

Even more interesting is some work on another protein CD33, found on immune cells and glia in the brain [ Neuron vol. 78 pp. 575 – 577, 631 – 643 ’13 ] A minor allele (21% frequency in human populations) of CD33 (SNP rs 3865444) protects against Alzheimer’s. The allele is associated with reductions in CD33 expression in microglia, and also with reduction in levels of insoluble Abeta42 in (Alzheimer’s) brain. The numbers of CD33+ microglia correlate with insoluble Abeta42 levels and amyloid plaque burden. So decreasing (or inhibiting) CD33 function might help Alzheimer patients.

Again the protective allele is only found in man. The great apes don’t have it just the major (nonprotective) allele.

Again, there is no way that having the allele directly improves your reproductive success. By the time it is protecting you, you’re infertile.

What in the world is going on? Why did alleles protective against Alzheimer’s arise in two very different proteins in the course of human evolution?

“There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.” — Mark Twain.

The reason these alleles probably arose gets us in to an ancient battle in evolutionary theory — what is the actual unit of selection? It may be the group rather than the individual. Face it, human infants and children are helpless for longer than other primates, and need others to care for them, for at least 5 years. Who better than grandma and grandpa? So the fact that with granny around more children survive to reproduce constitutes group selection (I think).

As Theodosius Dobzhansky said “Nothing in Biology Makes Sense Except in the Light of Evolution”