Wordless Wednesday



Is Alzheimer’s a prion disease?

Alzheimer’s disease affects more than 30 million people worldwide. One cause of this devastating type of dementia are tangles of a protein called tau. Tau usually binds to the cell’s inner skeleton, but in patients it groups together in brain cells and forms tangles, clogging them up. Other neurodegenerative diseases are also caused by tau, together they are called “diseases of tau” or tauopathies. Already 30 years ago, some researchers suggested that the cause for Alzheimer’s and other tauopathies could be a mechanism similar to prions – of mad cow disease fame. Prion-diseases like mad cow, Creuzfeldt-Jakob or scrapie are caused by small prion proteins that clump together. Prions come in different strains, which each cause different forms of clumps. Such clumps are “seeded”: one prion folds into an abnormal structure and causes other, normal, prions to also deform and clump together. Alzheimer’s and other tauopathies spread through networks of brain cells. This suggest that something toxic moves from one brain cell to the next, for example tangles of tau. Also a prion-like process of “seeding” has been suggested, with a tau tangle causing normal tau to deform . But conclusive proof of Alzheimer’s being a prion disease has been missing so far. In a paper in press in Neuron, researchers from the US and the UK show that tau acts like a prion.

Tau in a normal cell, and the formation of bundles in a cell of an Alzheimer's disease patient. Copyright: NIH

Tau in a normal cell, and the formation of bundles in a cell of an Alzheimer’s disease patient. Copyright: NIH

Scientists define prion diseases as “strains” of clumps that transmit into a cell or organism, can be extracted from a cell or organism and then when put back into a new cell or organism cause the same structure of clumps. In their work, the papers’ authors seek to show that a similar process is at work in Alzheimer’s disease. As the brain is a complex organ, scientists often use cells grown in a dish, in so-called cell culture, as a first start in their study. Here, the researchers made cells that produce a tau protein that glows yellow, but otherwise folds normally. When they added small tangles of tau into the cells, the yellow tau protein also joined the tangles. They then isolated colonies of cells with tangles, called clones, and allowed them to grow in single dishes. Different clones had different properties of tau tangles, like the size or position of tangles in the cell. The researchers then burst open clone cells, and put the cell solution into a dish with fresh cells with normal tau. The normal cells then form tau tangles, with the same properties as the clone used to infect them. These tau clones behave similar to prion strains, and the researchers call them tau strains.

The researchers then moved on to look at tau tangles in mouse brains. When they put cell solution into the brain of mice, the different strains cause differing tangle types in different neuron groups. Brain solution from mice infected with one strain caused newly infected mice to get the same tangle structure in the same neuron groups. When the researchers put tau tangles into a brain region called the hippocampus, tangles spread to regions whose brain cells project to or from the hippocampus. This shows that tau tangles spread from one brain region to others that are connected with it by their cells. Finally, when the researchers isolate tau tangles from mice and put them back into cells, they get back the same strain specific tangle structure they started out with.

As a final indicator of whether tau behaves like a prion, the researchers looked at different human tauopathies. For this, they used brain extracts from donated brains of patients who suffered from five different tauopathies, including Alzheimer’s. When extracts from different diseases are put into cells, different and distinct tangle types form. Different tauopathies with their specific disease characteristics are therefore caused by different strains of tau tangles.

For all intents and purposes, from this paper, it looks like tau behaves and is a prion. Strains can be extracted, form distinct clump types, and different strains cause different types of diseases. One important difference that sets Alzheimer’s apart from classic prion diseases like mad cow disease and scrapie is that Alzheimer’s is not infectious , and spreads only within an individual. The paper’s authors posit, however, that limiting the term prion to mean only infectious particles could artificially limit our view of prion diseases, and ignore a mechanism that unites a range of diseases. Also, over 95 percent of human prion disease cases appear to be genetic or spontaneous (sporadic) anyways, and are not linked to an infection, nevertheless they are seen as a prion disease. Does this have any implications for the treatment of Alzheimer’s and other tauopathies? Seen as there is currently no treatment for prion diseases, it might not seem so. But the observation that tau tangles spread from one neuron to the next gives a glimmer of hope. When tau spreads, it is briefly outside of the neuron. In the space outside the neuron, tau is exposed to potential new therapeutics, for example to prevent tangle spread, or to contain the infectious tau tangle in only a limited area of the brain. This paper puts the hypothesis that tau is a prion on firmer ground, and could be a step in the direction of developing a cure for Alzheimer’s – even if only by pointing out one potential angle of attack.

The original research appeared in Neuron: http://www.cell.com/neuron/abstract/S0896-6273%2814%2900362-6

sperm spirals to its goal

When you’re trying to get pregnant, after a while, cuddling afterwards will inevitably be replaced by the charming beetle pose – lying on your back, legs up in the air. All in the hope of getting the little swimmers on their way to their goal. On their journey through the cervix, uterus and the oviduct they cover a route thousand times longer than the length of a sperm cell. Also, while sperm might travel along in a current of fluid in the cervix and uterus, in the oviduct mucus flows in the opposite direction to the sperms itinerary. How sperm manages to stay on track and not stray is not known, but understanding this process would help in improving the odds of fertilization, both during natural conception and IV treatment.

Researchers from the University of Cambridge now show that human sperm swims similar to a fish swarm with their head facing the current. This rheotaxis allows fish swarms to adapt to counter flows. Using microfluidic devices, in which liquid is forced to flow through tiny channels, the researchers show that human sperm cells not just align against the counter flow, but move along the walls of the channels. The sperm cells end up spiralling along the edges of the oviduct. This increases the chance of meeting a potential egg and could so help the sperm cells find the egg. The researchers suggest that this could help in the design of artificial insemination, by for example optimizing the fluid used for fertilisation. Whether we can replace the beetle pose with something a tad more dignified is not known – yet.
Original paper in eLife: Rheotaxis facilitates upstream navigation of mammalian sperm cells – http://elifesciences.org/content/3/e02403