Lisbon Researchers Identify Tiny Antibody Fragments That Halt the Clumping of Alzheimer-Linked Tau Protein in Lab Cells, Though It Is Not a Treatment

A team at the Faculty of Sciences of the University of Lisbon (Faculdade de Ciências da Universidade de Lisboa, known as Ciências ULisboa) has identified tiny antibody fragments that interfere with the clumping of Tau, a brain protein whose build-up is a hallmark of Alzheimer's disease and several other neurodegenerative conditions. One of the fragments completely suppressed both the clumping and the spread of Tau in a laboratory cell model, the faculty said in a release on 12 October.

The faculty is explicit that this is not a treatment. The work is at a fundamental stage, and for now the fragments are research tools for studying how Tau aggregates and propagates, not a therapy that could be given to patients.

What the team found

The study, titled "Chaperone-inspired nanobodies enable pathway-selective control of Tau self-assembly", was published online on 28 September in Communications Biology, an open-access journal in the Nature Portfolio group. The journal is sharing it as an early, peer-reviewed accepted version, which may still be edited before the final version appears.

The fragments are nanobodies: very small antibody pieces that can latch onto a specific protein. The team had developed them to study a different molecule, S100B, a protein that occurs naturally in the brain and helps keep other proteins from clumping. Unexpectedly, some of those nanobodies also recognised Tau directly.

According to the faculty, the researchers identified three nanobodies able to inhibit Tau aggregation. The paper's abstract says the selected nanobodies bind both single Tau molecules and the fibrous "seeds" from which larger clumps grow, and that their effect increased with concentration. The nanobodies appear to act on different stages of the process. One of them strongly suppressed the step in which existing fibres speed up the formation of new ones, and it stopped Tau seeding in a biosensor cell model. The faculty's release describes the standout nanobody's effect in cells as total suppression.

"In this work we discovered that small antibody fragments developed to study a protective brain protein can also act directly on Tau and interfere with its aggregation," said Cláudio M. Gomes, the Ciências ULisboa professor who coordinated the study (translated from Portuguese). The team calls the molecules "chaperone-inspired nanobodies", after the chaperone proteins that help other proteins stay stable and working.

Who did the work, and what comes next

The research was carried out in Gomes's laboratory at the Institute of Biosystems and Integrative Sciences (Instituto de Biossistemas e Ciências Integrativas, BioISI), based at the faculty. The first author, Margarida Simões, is finishing a doctorate in biochemistry there. Collaborators came from the i3S health research institute at the University of Porto, the University of Lille in France and the Vrije Universiteit Brussel in Belgium. According to the paper, the main funder was Portugal's Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia, FCT), with further support from European Union programmes.

The faculty sets out two next steps:

• testing whether the nanobodies act on Tau clumps taken from human brain tissue;
• checking, in models of neurons, whether reducing Tau aggregation protects the cells from the toxic effects linked to it.

Neither the release nor the paper's abstract reports any testing in animals or people. The paper's authors present the approach as a way of using the body's own anti-clumping proteins as templates for finding new binders against proteins that aggregate. For families living with the disease today, the practical debate in Portugal is elsewhere: the charity Alzheimer Portugal has been pressing the state to fund the new drugs that slow the disease.