Taming Tau

As a companion to a recent NYAS meeting summary pointed out at the Longevity Meme, here is another on the same topic: the biochemistry of Alzheimer's disease.

In the modern history of drug discovery in Alzheimer's disease (AD), amyloid-β (Aβ) has played the diva's role: center stage, with top billing - and difficult to manage. Aggregates of this peptide, which form amyloid plaques, are evident in the brains of people who die of or with Alzheimer's disease, making it an obvious target for therapeutics. But simply reducing amyloid buildup in the brain hasn't been easy. Meanwhile, evidence mounts that the microtubule-associated protein tau is an equally important player in this disease process.

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Right now, the prevailing idea is that tau, which under normal conditions stabilizes microtubules, becomes hyperphosphorylated and undergoes conformational changes in Alzheimer's disease. Tau is normally phosphorylated - it can undergo phosphorylation at up to 19 sites, affecting the kinetics of how it binds to microtubules - but in AD, phosphorylation expands to almost all possible sites, about half of which are serine/threonine residues followed by a proline. A cluster of pathogenic events is associated with this change: tau, normally highly soluble, accumulates in neurites and forms insoluble tangles. Tau also moves from the axons into the somatodendritic compartment of the cell. The protein appears to lose its ability to bind to and stabilize microtubules. Ultimately, cells stop working properly and die.

Why this happens, and how these various steps are causally linked, is a flourishing field of research.

From where I stand, admittedly far from the action, Alzheimer's has the look of a clump of related conditions or disease-causing processes. Many roots leading to a similar and unfortunate end state would explain a great many of the contradictory or seemingly unrelated lines of research to date.

Watching reports from the front is a good way to obtain an impression of the scale of our biochemistry - it's immensely complex. Equally, we should be impressed by the degree to which modern technology and the scientific community are up to the tasks at hand. The secrets of Alzheimer's, just as for the rest of our inner workings, won't remain secret for many more years. Along the way, scientists will have accumulated the working knowledge of the brain that we'll need to help extend healthy life span in the near future.

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