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Tracking and attacking tau

Long considered a second-string player in Alzheimer's, the tau protein is now moving into place of primacy for its role in neuronal death and its correlation with cognitive decline.

Tau is the second aberrant protein implicated in Alzheimer’s pathogenesis. Its native function is to promote the assembly and stabilization of microtubules, the tubular structures that provide both support and transport within a cell.

Neuronal tau appears to localize in axons, where it seems to promote a more flexible microtubule than is seen in other cells. Along this axonal highway travel all the cargoes that make the cell’s life possible. Lipids, proteins, mitochondria, and vesicles full of neurotransmitters move from the cell body toward the dendrites. Proteins destined for degradation travel the other way, into the cell body where they are sequestered in lysosomes and broken down.

At any one time, the largest portion of tau is bound into the microtubule. Its stabilizing force depends on how many phosphate molecules attach to it. When tau becomes hyperphosphorylated, however, it loses the ability to attach to microtubules. These then begin to collapse, interrupting axonal transport. The collapse damages interneuronal communication. The now-unbound tau in the cell misfolds and aggregates into fibrils that tangle together, eventually killing the neuron.

It’s unclear what jump-starts hyperphosphorylation and misfolding. But at some point, extracellular propagation – called seeding – becomes apparently self-perpetuating. This also is a mystery, as the renegade protein moves from cell to cell almost like a prion in an infective disease.

Although tau has long been identified as a characteristic lesion of Alzheimer’s, its pathogenic role has not been as fully explored as that of amyloid. The brand-new ability to image tau with PET radioligands has literally shed new light on this area.

Like amyloid plaque deposition, tau tangling begins years before symptoms. And like amyloid, tau is present in the brains of many cognitively normal elderly. Scientists differ on which protein first becomes dysregulated, whether they happen simultaneously, and even whether that timing matters.

What is very clear is that cognitive decline closely tracks the burden of tau tangles. While there are no cognitive correlates with amyloid, cognition decreases almost linearly as tangle burden increases. And, because both lesions are always present in Alzheimer’s, this finding of cognitive correlation suggests that the clinical manifestation of Alzheimer’s may occur only when tau and amyloid move into the same region.

Five drugs  representing three therapeutic strategies (microtubule stabilization, fibril antiaggregation, and immunotherapy) are being investigated in clinical trials; others are still in early development.

LMT-X, a derivative of methylene blue, has advanced to phase III study after positive results from its exploratory phase II study.

Two active antibodies and one passive antibody are all in phase I study. Also in phase I is TPI 287, a molecule that binds tubulin and stabilizes microtubules. Interestingly, this is a derivative of the taxane anticancer drugs. Because of its ability to cross the blood-brain barrier, TPI 287 is also being investigated as a treatment for primary and metastatic brain tumors.

 

Photo credit: National Institutes of Health

01/14/16 | By: Michele G. Sullivan

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