Researchers at the Institute for Neurosciences, a joint centre of the Miguel Hernández University of Elche and the Spanish National Research Council, have identified elevated levels of the active form of the protein meprin-β in the brain and cerebrospinal fluid of Alzheimer’s disease patients, providing new insights into beta-amyloid processing.
Meprin-β Elevation in Alzheimer’s Brain Tissue
Led by Javier Sáez Valero, a research team at the Altered Molecular Mechanism in Alzheimer’s Disease and Dementia laboratory found that the active form of meprin-β increases specifically in advanced stages of the neurodegenerative condition. According to the study published in Alzheimer’s Research & Therapy, scientists analyzed frontal cortex samples categorized by Braak stages, a scale used to describe the progression of pathology in the brain.
The investigation separated the immature, inactive form of meprin-β from its mature, active form. Results showed that the active enzyme increased during advanced Braak stages. Furthermore, the team detected a parallel rise in MEP1B messenger RNA, which provides the genetic instructions for producing the protein, at intermediate and advanced stages.
Did you know? Cerebrospinal fluid is obtained via lumbar puncture, allowing clinicians and researchers to analyse molecules related to processes occurring in the nervous system.
Cerebrospinal Fluid Analysis and Patient Biomarkers
Beyond brain tissue, the research group examined cerebrospinal fluid samples. According to findings detailed in the journal, active meprin-β levels were higher in individuals with Alzheimer’s disease.
“Finding increased levels of the active form of meprin-β in cerebrospinal fluid raises new questions about its relationship with the changes that occur during the disease and its potential use as an indicator,” says Javier Sáez Valero, the study’s principal investigator.
Until now, much of the attention focused on BACE1 as a relevant β-secretase in Alzheimer’s disease. This new work highlights meprin-β as an additional enzyme that can act as a β-secretase, which may influence amyloid precursor protein processing.
Experimental Links to Beta-Amylolyd Pathology
To test whether beta-amyloid accumulation drives meprin-β increases, investigators expanded their study to animal models and laboratory cell cultures. Sergio Escamilla, the first author of the study, noted that cerebrospinal fluid analysis from transgenic rats that develop pathology associated with beta-amyloid accumulation also revealed elevated active meprin-β.
In parallel experiments, human neurons derived from induced pluripotent stem cells were exposed to the beta-amyloid peptide Aβ42. When treated with this peptide, the laboratory-grown neurons produced a significant increase in meprin-β levels.
“When we expose human neurons to beta-amyloid, we also observe an increase in meprin-β,” explains Sergio Escamilla. “This provides an experimental link between one of the hallmarks of Alzheimer’s disease and the alteration we have found in patient samples.”
Pro Tip: Researchers utilize induced pluripotent stem cells to generate neurons in a controlled laboratory setting, enabling direct observation of cellular responses to specific Alzheimer’s disease pathologies.
Collaborative Research Network and Funding Support
The international study brought together institutions including the University Medical Center Mainz in Germany, the University of Barcelona, and the University of Gothenburg in Sweden. Participating Spanish researchers are also affiliated with the Biomedical Research Networking Center on Neurodegenerative Diseases and the Institute for Health and Biomedical Research of Alicante.
Financial backing for the project came from multiple public and scientific agencies, including the Fondo de Investigaciones Sanitarias, the European Regional Development Fund of the European Union, the CIBERNED network of the Carlos III Health Institute, the CIAICO programme of the Generalitat Valenciana, the Ministry of Science, Innovation and Universities, the State Research Agency, and the Severo Ochoa Programme for Centres of Excellence.
Frequently Asked Questions
What is meprin-β?
Meprin-β is an enzyme that acts as a β-secretase, meaning it can process amyloid precursor protein, which is linked to the production of beta-amyloid peptides found in Alzheimer’s disease.
How does meprin-β change in Alzheimer’s patients?
Research shows that the mature, active form of meprin-β increases in both the brain tissue and cerebrospinal fluid of individuals with Alzheimer’s disease, particularly during advanced pathological stages.
Why is finding meprin-β in cerebrospinal fluid important?
Cerebrospinal fluid can be sampled via lumbar puncture, meaning that identifying disease-associated molecules here opens pathways toward potential future use as an indicator.
What role did laboratory stem cells play in this study?
Scientists used human neurons derived from induced pluripotent stem cells and exposed them to beta-amyloid peptide Aβ42, observing a direct cellular increase in meprin-β.
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