Researchers from the University Institute of Biomarkers of Molecular Pathologies (IBPM) at the University of Extremadura (UEx) have found a new biomarker in Alzheimer’s disease of sporadic origin called STIM1 protein. Its involvement in neuronal deterioration has been proven thanks to the CRISPR-Cas9 technique.

The objective of this research is to develop a model to study this pathology of sporadic origin, that is, it is not due to a hereditary genetic mutation. While the hereditary type of Alzheimer’s is responsible for around 5% of cases, it is believed that in 95% it has an unknown origin.

Animal models already exist in hereditary Alzheimer’s, as the genes linked to this disease are already known, said Francisco Javier Martín-Romero one of the authors of the study.  However, in non-familial Alzheimer’s there are no models that allow us to study the development of pathology, he added.

Researchers from Extremadura analyzed samples of damaged brain tissue from a region of the hippocampus called the middle frontal, which is where the alterations caused by Alzheimer’s are initially observed. These clinical samples have been analyzed and compared with healthy tissue from patients of the same age.

As a result of this comparative study, scientists have found a deficiency of the STIM1 protein in brain tissues of patients with the disease. “We have been working with this protein for 10 years, but we did not expect these results in sporadic Alzheimer’s,” said Martín-Romero.

The next step has been to observe the involvement of this protein STIM1 in the neurodegeneration of the neuronal cell, and they have done it through genetic editing system CRISPR, known as the genetic cut and paste.

Researchers have applied a strategy to eliminate the expression of the STIM1 gene in the neuroblastoma cell line SH-SY5Y by editing the genome through CRISPR-Cas9, using an in vitro model to examine the phenotype of neuronal cells deficient in STIM1.

In this case, CRISPR silences the gene that allows the expression of the STIM1 protein in the neuron. Thus, we have been able to simulate what happens in the neuron without that protein and we have observed alterations very similar to what happens in tissues with Alzheimer’s, “the researcher said.

Until now the effects of the deficiency of this critical protein in the sporadic type were not known, so this research provides a new biomarker of the disease, indicator of the stage of the neurodegenerative process.

Novelty in the treatment

One of the observed alterations, due to the deficiency of STIM1, occurs in the transport of calcium ions through the plasma membrane of the neurons. “This calcium is necessary for the cell to perform all its functions, and an alteration in this process affects the entire physiology of the cell, ultimately causing its death. The cell is not able to stop the transport of calcium, which is deregulated and out of control,” said Martín-Romero.

The researcher points out that this transport occurs through voltage-operated calcium channels. Channels that can be blocked with drugs based on dihydropyridine, a molecule that blocks L-type calcium channels, sensitive to voltage. In this sense, the team of researchers has been able to stop in vitro cell death with dihydropyridine-based drugs, which is an important novelty in the treatment of Alzheimer’s.

The next step is to work with pluripotent stem cells and differentiate them into neurons, first of mice and then humans, so that a model can be developed. This will allow us to describe how the absence of stimulation or reduction of the STIM1 protein conditions cellular aging in sporadic Alzheimer’s.


Source: SINC