Antibodies for the diagnosis and treatment of early stages of Alzheimer's disease

Under normal conditions, tau protein is necessary for the full functioning of the brain. However, recently there is more and more evidence indicating that in Alzheimer's disease and other neurodegenerative diseases, this protein does not just lose the ability to perform its functions, but transforms into a villain that destroys brain cells.

The use of antibodies developed by specialists of the Beth Israel Medical Center, working under the leadership of Kun Ping Lu and Xiao Zhen Zhou, for the first time provided an opportunity for a clear distinction between normal and pathologically altered forms of tau protein. Moreover, scientists have found that only a pathological isoform of this protein is registered in the neurons of patients with Alzheimer's disease (the most common cause of dementia) already at the early stages of the disease.

In healthy brain tissue, tau protein participates in the assembly and stabilization of the microtubule skeleton, which provides a unique shape of neurons. The functioning of this protein is accompanied by the attachment and detachment of phosphorus residues from its molecule. Phosphorus residues occur in the form of two isoforms: trans isoforms (direct) and cis isoforms (c).

Researchers were aware that abnormal phosphorylation of tau protein is involved in the pathogenesis of Alzheimer's disease, as well as that the enzyme Pin1 (prolylisomerase) in a number of animal models prevents the development of this disease.

They suggested that during the normal course of the aging process in healthy people, the Pin1 enzyme returns the cis isomers of phosphorus residues attached to the tau protein to the normal trans isoform. Therefore, with a decrease or absence of activity of this enzyme, an abnormal isoform of tau protein accumulates, the end result of which is the development of Alzheimer's disease.

To test this hypothesis, they developed a complex of protein fragments similar in shape to different isoforms of tau protein, and used them as antigens for the formation of antibodies to trans- and cis-isoforms of the protein.

Using these antibodies, they analyzed the content of tau protein in healthy brain tissue samples and the brains of patients with different stages of Alzheimer's disease. As a result, it was not possible to identify any isoforms of tau protein in healthy brain tissue samples, whereas for tissue samples of patients with early stages of dementia (moderate cognitive impairment), an accumulation of the cis isomer of this protein was observed. Moreover, they found that the progression of the disease into Alzheimer's disease is accompanied by a selective accumulation of the cis-isoform of the protein in the affected neurons localized in the regions of the brain responsible for memory.

Subsequent experiments have shown that the trans isoform of tau protein, as well as the unphosphorylated protein, ensures the formation of microtubules and is resistant to the formation of strands. The cis isoform of the protein, on the contrary, is characterized by opposite qualities.

During the final series of experiments on cell cultures and animal models, the researchers demonstrated that an increase in the level of the Pin1 enzyme can prevent the accumulation of a pathological form of tau protein, while a decrease in its concentration contributes to the formation of neurofibrillary cords and nodes.

The researchers believe that their proposed approach, based on the introduction of antibodies specific to the abnormal isoform of tau protein, will allow the development of methods for the early diagnosis and treatment of Alzheimer's disease and, possibly, other neurodegenerative diseases.

Article by Kazuhiro Nakamura et al. Proline Isomer-Specific Antibodies Reveal the Early Pathogenic Tau Conformation in Alzheimer's Disease published in the journal Cell.

Evgeniya Ryabtseva
Portal "Eternal Youth" based on the materials of Beth Israel Deaconess Medical Center:
Researchers develop novel antibodies to diagnose and treat Alzheimer's disease.

03.04.2012