Anti-tau antibodies: what is the rationale, and how far have they come?

New techniques can measure tau in interstitial fluid

Monomeric tau and aggregated tau are both present in interstitial fluid

To test the theory that tau can escape cells, David Holtzman and his group at the Washington University School of Medicine, USA, developed a microdialysis technique that can measure tau levels in the hippocampal interstitial fluid (ISF) of awake, freely moving mice. Monomeric (i.e., un-aggregated) tau was detected outside of cells, in the ISF, at appreciable concentrations. In previous studies, aggregated tau has also shown an ability to cross cell membranes into the ISF, and thereby to transfer between cells.

But is extracellular tau involved in AD pathology, by spreading tau aggregates to different parts of the brain? To answer this question, the microdialysis technique was used in ‘P301S Tg’ mice – a race afflicted by tau tangles and brain atrophy.

The P301S Tg mice were tracked as their tau pathology progressed. Early on, the ISF monomeric tau level was five-times higher in P301S Tg mice than in normal mice. As tau aggregates began to form in the ISF, the monomeric tau level in the ISF decreased markedly. This led to the theory that tau aggregates, having escaped from brain cells, act as ‘seeds’ – sequestering monomeric tau from the ISF, and thereby propagating tau pathology.

Extracellular tau aggregates play a central role in the development of AD pathology

The spread of tau pathology is driven by synaptic activity

The logical next question is, what causes tau to be released into the extracellular fluid? Dr Holtzman hypothesised that synaptic activity may be the answer, and devised another series of microdialysis experiments.

As expected, increased neuronal activity led to increased ISF monomeric tau levels. In contrast, decreased neuronal activity did not reduce ISF tau levels. This was explained by the fact that the brain is slow to remove tau from the ISF (it has a half-life of approximately 11 days); thus, levels remain high even with no further supplementation.

So, armed with this knowledge, could the spreading of tau be blocked by antibodies?

Anti-tau antibodies show promise in preclinical models

Immunotherapy can target transcellular tau aggregate propagation

Antibodies are normally unable to enter cells. But, if the propagation of tau pathology is driven by extracellular seeds, then this process could potentially be blocked by antibodies. And, since 2007, several studies in mouse models have shown that immunisation against tau is beneficial.

Dr Holtzman’s lab screened a number of potential anti-tau antibodies in vitro, with three progressing to animal tests. When infused directly to the brain of P301S Tg mice, the antibodies markedly reduced levels of aggregated tau, as well as improving cognitive deficits. The most promising candidate was then tested via peripheral administration, where it decreased insoluble tau levels, decreased brain atrophy, and improved motor performance.

These are exciting results, meriting the investigation of anti-tau antibodies in humans. Today, anti-tau antibodies are under investigation in Phase I clinical trials.

How do these antibodies work?

The precise mechanisms by which anti-tau antibodies reduce ISF tau levels are still unknown, but clues can be ascertained by studying blood tau levels.

Although tau is produced and released in the brain, it is able to pass into the blood. Here, it is rapidly cleared – over a matter of minutes. After administration of anti-tau antibodies, however, the amount of tau in the blood increases. This increase is attributed to the presence of antibody–tau complexes, which take many hours to be cleared away.

So, while questions remain, anti-tau antibodies show great promise, and – if successful in clinical trials – may represent an important disease-modifying opportunity in AD.