A Cleanser For Tau Clumps

Alzheimer's disease is caused in part by protein clumps including amyloids and tau fibrils. We have an enzyme for that!

The iPhone appeared a decade ago, and gained ground so definitively because it provided a general platform (and large screen) for which others could develop rich applications. The ramifying copying, diversification, and specialization of those apps is reminiscent of evolution in general, and particularly of the "apps" present in every cell. Proteins are based on a generic/genetic platform of DNA coding and RNA translation, and self- assemble into countless shapes and sizes, complexes and pathways, to do all sorts of tasks to make life better for the organism. Where once there must have been very few or even none (in the RNA world), proteins have diversified over evolutionary time by endless rounds of copying, stealing, mutating, and specializing to constitute our current biospherical profusion.

Our bodies are filled with protein apps that generally keep their heads down and do their work without complaint. But a few can make trouble. Most notorious are the prions, which, as bizarrely misfolded versions of natural, functional proteins, can encourage other proteins to join them on the dark side, and even infect other organisms, causing unusual brain diseases and panics over epidemic transmission. Less notorious, but far more devastating, are various dementias such as Alzheimer's. These appear to be caused by the accumulation of junky proteins which clog cellular processes, and eventually kill brain cells, destroying the organ from within. The exact cause of this accumulation and how, or even whether, it kills cells are both still under study, but deposits of this junk (amyloid plaques and tau tangles/fibrils) are universally diagnostic of these dementias and prime candidates for research and treatment.

Proteins are constantly growing old and getting sent to the garbage, in all cells. The problem with the Alzheimer's-related proteins seems to be that they escape this disposal process, either because they accumulate too rapidly, or because they condense into crystalline entities that can no longer be pried apart by the various chaperones and other proteins that constitute our sanitary services. A recent paper discusses one human protein that seems able to clean up junk composed of the tau protein, even at its worst, and might be the kind of thing that could be injected or increased by genetic therapy to treat such syndromes.

Proline, the only amino acid that cyclizes back to the peptide chain, creating kinks in protein structures. The bond that Cyclophilins wrench back and forth is resonance-stabilized, making this trick a bit harder than it looks.

Cyclophilins are a class of protein chaperone (which are proteins that assist the folding of other proteins) that catalyze the switching of proline peptide bonds from cis to trans (see above). Proline is the stiffest amino acid, and plays a major role in generating kinks, turns, and other rigid aspects of protein structure. So cyclophilins help loosen up such structures and get proteins back on track if they have gone down a tangled path. That seems to be the case with tau, which is the crystallized conformation of fragments of a protein that in its normal state is a membrane protein thought to participate in synapse formation. Naturally, the accident of causing dementia in old age is, in evolutionary terms, a minor issue as it takes place well after reproduction has occurred, allowing such evident genetic defects to persist in our population.

The authors diagram how the tau protein (red and gray) might get its turns loosened up by CyP40, (black), allowing the tight beta-sheet structure to dissolve.

The authors run through a series of experiments to show that one cyclophilin, CyP40, is particularly effective in dissolving tau fibrils, one form of protein aggregation seen in Alzheimer's. It dissolves them in the test tube, it dissolves them when infected via a virus into the brains of mice, and it reduces neuron damage and cognitive decline that happens in these mice, which are engineered with extra human tau protein expression, and exhibit a rapid dementia-like progression.

When CyP40 is added (red), tau fibers can be dissolved in the test tube. FKB51 and -52 are other cycophilins that do not have this particular activity, serving as controls.

Engineered tau-expressing mice (red) can have their cognitive abilities improved after a virus carrying the CyP40 expressing gene was injected into their brains. The Y-axis is rate of errors in a water maze test, done at 3 months, which is relatively late in life for these mice.

It is an impressive and promising piece of work, to go from molecular structure to medically significant function, though it took 19 authors to get there. One notable aspect of this protein is that it does not require ATP- its mechanism is very efficient and the protein is relatively small- properties that are helpful when the targeted protein clump is outside of cells or in dying or dead cells. It is also part of family of 41 such proline isomerase enzymes in humans, so others may be found that operate on the other major culprit in Alzheimers, amyloid beta protein. On the other hand, we already encode and make Cy40 and it relatives. Why are they not being turned on and expressed in our brains where and when they are so desperately needed? The authors are silent on that score, and have taken out a patent for the therapeutic possibilities of the exogenously supplied version.

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