Researchers identify a mutation that alters Alzheimer's disease progression

This work, published in Journal of Alzheimer’s Disease, has characterized a genetic variant in SIRPβ1 gene, which affects the way in which the immune system fights against beta-amyloid deposits, the cause that leads to this pathology.

In conducting this work, a longitudinal study was carried out using epidemiological samples of more than 1,300 patients from Malaga and Barcelona, evidencing the role of this mutation in the cognitive decline of those affected. However, it was found that it does not represent a risk factor in itself for Alzheimer's disease.

“All human beings have the same genes, but there are variants of each one that make us different. Different external appearances and, also, different physiologies and metabolisms”, explains José Luis Royo, Professor of the Department of Surgical Specialties, Biochemistry and Immunology.

The UMA scientist points out that an analysis of the presence of this variant in the SIRPβ1 gene showed that 30 percent of the general population has one mutation copy and 4 percent of the population has both copies affected. “Therefore, we are talking about a variant that is very present in the general population,” he says.

Dual effect
The research, which involves scientists from more than 50 different entities, shows that the mutant variant changes the structure of the protein and how this alters the behavior of brain immune cells, called microglia.

“When we studied its role in the course of the disease, we found out that it has a dual effect depending on the disease stage: at the beginning, in patients with mild cognitive impairment, the mutation increases the conversion risk to Alzheimer's disease, so it has a detrimental effect in early stages; however, when dementia is established as such, those mutation carriers show slower cognitive decline, suggesting a beneficial effect among these patients”, clarifies the UMA researcher.

Royo points out that, therefore, the mutation affects the immune system response to beta-amyloid deposits, probably to the neuroinflammation process, which is a physiological response in the early stages but harmful if it becomes chronic as the disease progresses.

Thus, this dual effect of the genetic variant, he says, suggests that this cell signaling pathway should be inhibited during the early stages of the disease, but it should be stimulated in patients in more advanced stages, to chemically mimic the effect generated by the mutation. “This finding opens the door to a new biochemical therapeutic target that, in the future, could be synthesized with a drug”, he concludes.

Currently, researchers keep working to characterize the effect of this mutation at a higher level of complexity and have designed a system to look for modifiers of this cell signaling pathway.

Multidisciplinary scientific team
‘An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response’ is a multidisciplinary work in which 100 researchers from more than 50 different entities have participated, including the Andalusian Institute of Neuroscience (IANEC) of Malaga, the Faculty of Science of the UMA, the ACE Foundation and the Centre for Genomic Regulation (CRG) in Barcelona, the Institute of Biomedicine of Seville (IBIS) and the Andalusian Center for Developmental Biology (CABD), among many others.

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NOTES FOR EDITORS
Article
“An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer’s Disease Cognitive Decline Altering the Microglial Response,” by J.M. García-Alberca, I. de Rojas, E. Sanchez-Mejias, D. Garrido-Martín D, et al. (https://content.iospress.com/articles/journal-of-alzheimers-disease/jad231150), Journal of Alzheimer's Disease, Volume 98, Issue 2, published by IOS Press. 

About the Journal of Alzheimer’s Disease
Now in its 27th year of publication, the Journal of Alzheimer’s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment, and psychology of Alzheimer’s disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease, and clinical trial outcomes. JAD has a Journal Impact Factor of 4 according to Journal Citation Reports (Clarivate, 2023). The journal is published by IOS Press. j-alz.com

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