Tau protein modifications emerging in early stages of Alzheimer’s disease disrupt cellular cytoskeleton protection and enable its degradation

In the early stages of Alzheimer’s disease, changes occur in a key protein called tau, which normally forms a protective layer around the neuron’s internal skeleton. When modified, tau loses its protective function, leading to neuron death. The new perspective presented by a Czech-French research team uncovers the molecular consequences of tau modifications, opening new avenues for the diagnosis and treatment of early-stage Alzheimer’s disease and related disorders.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the gradual loss of neurons in specific brain regions, resulting in progressive decline of memory, cognition, and self-care abilities. Before neuronal degeneration occurs, molecular changes appear in several proteins. One key player is the tau protein—but the precise consequences of its early molecular alterations have remained poorly understood.

A protective “coat” that falls apart

Like many other proteins, tau binds to microtubules—the filamentous structures forming the cell’s “skeleton”—and creates a protective coating around them to prevent their disintegration. In a new study, researchers from two institutes of the Czech Academy of Sciences, Charles University, and France have described at the molecular level how chemical modification of tau (phosphorylation) disrupts the formation, cohesion, and protective function of tau envelopes, leading to faster microtubule breakdown. “Our results show that once tau becomes phosphorylated, the protective envelopes it forms around microtubules lose their ability to safeguard them effectively and become more prone to disruption,” explains Valerie Siahaan, first author of the study from the Institute of Biotechnology CAS.

Damage begins earlier than expected

A key finding of the study is that microtubules may start to disintegrate even before tau fully detaches from them—a step previously considered essential for disease progression. “Our study demonstrates that phosphorylation alone disrupts the internal cohesion of tau envelopes, creating ‘holes’ that allow enzymes degrading microtubules to penetrate. Thus, microtubule destabilization begins earlier than previously thought, before phosphorylated tau detaches completely and starts to accumulate in neurons,” explains Martin Balaštík, one of the corresponding authors from IPHYS.

A new view of the early stage of Alzheimer’s disease

The findings provide a new explanation for one of the hallmarks of Alzheimer’s pathology—the breakdown of microtubules in neurons. The study suggests that this damage may occur early, as a result of the loss of tau’s protective function, rather than only after its complete detachment or the formation of large tau aggregates (neurofibrillary tangles) typical of later disease stages.

By uncovering the mechanism through which tau phosphorylation undermines microtubule protection, the study opens new paths for exploring the early molecular events in Alzheimer’s disease and related disorders—and potentially for developing therapeutic strategies focused on preserving neuronal stability.

The work was carried out in international collaboration between scientists from the Institute of Biotechnology CAS, the Institute of Physiology CAS, Charles University in Prague, and the Institut Curie in France, and was published in Nature Chemical Biology.

Reference:
Siahaan V., Weissova R., Karhanova A., Lanska E., Ruiz-Estrada M. J., Pukajova B., Dostal V., Henriot V., Janke C., Libusova L., Braun M., Balastik M., and Lansky Z. Tau phosphorylation impedes functionality of protective tau envelopes. Nat Chem Biol (2026). IF = 15.7; DOI: 10.1038/s41589-025-02122-9