Published on: Jun 19, 2025
Although it is known that Alzheimer's can begin up to 20 years before the first symptoms appear, the lack of knowledge about how it progresses prevents the development of effective treatments, as well as a clear diagnosis to address this neurodegenerative disease, whose origin is also unknown in most cases." This is according to UMA researcher David Baglietto, who specializes in the study of risk factors—genetic, environmental, and lifestyle—that can influence, among others, the development and progression of this pathology.
In the search for a possible therapeutic target to halt the progression of this disease, a scientific team from the Department of Cell Biology, Genetics and Physiology at the UMA, belonging to the NeuroAD group - which in turn is part of CIBERNED and IBIMA-BIONAND Platform -, has made progress in understanding the pathogenetic mechanisms responsible for the progression of this pathology in the brain, identifying different factors involved in the propagation processes.
To do so, they compared postmortem brain samples from Alzheimer's patients provided by the University of Irvine (California, United States) with samples from transgenic models of the disease, showing that the progression of the disease occurs differently in both cases, as the cells do not respond the same way in each model. "The beta-amyloid species (seeds) that are generated are different and have distinct pathogenic properties," says Baglietto, who led this work. The results of this research, recently published in the scientific journal 'Aging Cell' , could therefore be of clinical interest for the development of potential therapies that modulate the course of Alzheimer's disease.
In this sense, Baglietto explains that, for example, the immune response is different, as is the appearance of synaptic damage or the way in which Alzheimer's disease is enhanced. "This finding sheds new light on the fact that many of the therapies that work successfully in preclinical models later fail to do so in humans," he clarifies.
Toxic aggregates in the brain
According to the researcher from the Faculty of Sciences at the UMA, one of the fundamental characteristics of this disease is the significant accumulation of toxic protein aggregates in the brains of patients. "These brain accumulations form as a result of abnormal folding of soluble proteins and their subsequent aggregation, which can occur due to multiple causes that are still unknown and following different pathogenic mechanisms," he points out.
The scientist points out that, once initiated, these abnormal conformations are capable of spreading and inducing these same aberrant foldings in other soluble proteins, disseminating the disease to different brain regions. "For this reason, it is extremely important to know which protein isoforms or foldings are the most pathogenic and to determine how this spread occurs."
This study has shown that brain samples from Alzheimer's patients contain pathogenic isoforms of the beta-amyloid peptide that are more likely to promote the formation of senile plaques toxic protein aggregates than in the animal models of the disease used in this research.
International multidisciplinary team
This research has been coordinated by the UMA over the past four years, based on the work of Juana Andreo, a doctoral student in the Cell Biology Department. Also participating were Dr. Antonia Gutiérrez the lead researcher at NeuroAD, Dr. Cristina Nuñez, Dr. Laura Trujillo, and Dr. Juan Antonio García, and researchers Miriam Bettineti and Cynthia Campos.
It also includes the collaboration of scientists from the United States, from the University of California and the University of Texas, and from Italy, specifically from the Institute of Crystallography of Catania. Its 21 authors also include contributions from IBIMA-BIONAND Platform, the CIBER for Neurodegenerative Diseases (CIBERNED), and the Integrative Center for Biology and Applied Chemistry of Bernardo O'Higgins University (Chile), among others.
The specialists involved assure that these studies are "very important," since a greater understanding of the factors, cell types, and protein isoforms (seeds) responsible for promoting aggregative processes could represent an "excellent" therapeutic target that would slow or halt the pathogenetic progression of Alzheimer's disease, achieving a treatment capable of modifying its progress, which "has not yet been successfully achieved."
As next steps, the University of Malaga suggests improving experimental models that reproduce the disease, as well as "humanizing" certain genes to better reproduce the human pathology.
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