Alzheimer's patients show elevated active meprin-β in brain and cerebrospinal fluid

by Elena Garrido, Miguel Hernandez University of Elche

edited by Swati Mestri, reviewed by Robert Egan

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A team from the Altered Molecular Mechanism in Alzheimer's Disease and Dementia laboratory, led by Javier Sáez Valero, a researcher at the Institute for Neurosciences (IN), a joint center of Miguel Hernández University of Elche (UMH) and the Spanish National Research Council (CSIC), has identified increased levels of the protein meprin-β in the brain and cerebrospinal fluid of people with Alzheimer's disease.

The results, published in Alzheimer's Research & Therapy, show that the active form of this protein is elevated, providing new evidence of its possible relationship with processes associated with beta-amyloid, one of the hallmarks of the disease.

Alzheimer's disease is characterized, among other changes, by the accumulation of beta-amyloid in the brain. This peptide is generated when amyloid precursor protein (APP) is processed by different enzymes. One of them is BACE1; however, other enzymes can also act as β-secretases, including meprin-β.

"Until now, much of the attention has focused on BACE1 as a relevant β-secretase in Alzheimer's disease. Our work shows that there is another protein, meprin-β, whose active form is increased in the brain and cerebrospinal fluid of people with this disease," explains Sáez Valero, the study's principal investigator.

A protein in two forms

Meprin-β is an enzyme that can exist in different forms. To investigate what happens during Alzheimer's disease, the researchers analyzed its immature, inactive form separately from its mature, active form.

The team studied samples of the frontal cortex from people at different stages of the disease and compared them with samples from people without Alzheimer's disease. The samples were classified according to Braak stages, a scale used to describe the progression of pathology in the brain.

The results showed that the active form of meprin-β increases in the more advanced stages of the disease, corresponding to more advanced Braak stages, while this increase was not observed in the early stages. In addition, the researchers detected an increase in MEP1B messenger RNA, which contains the instructions for producing this protein, at intermediate and advanced stages.

The team also analyzed cerebrospinal fluid samples and detected increased levels of the active form of meprin-β in people with Alzheimer's disease. This finding is particularly relevant because cerebrospinal fluid is obtained through a lumbar puncture and can be used to analyze molecules related to processes occurring in the nervous system.

"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," explains Valero.

The relationship with beta-amyloid

To investigate whether the increase in meprin-β could be related to beta-amyloid accumulation, the team analyzed cerebrospinal fluid from transgenic rats that develop pathology associated with beta-amyloid accumulation. They also observed an increase in the active form of meprin-β in these animals.

The researchers then used human neurons derived from induced pluripotent stem cells (iPSCs), which can be used to generate neurons in the laboratory and study their response under different conditions. When these cells were exposed to the beta-amyloid peptide Aβ42, the researchers observed a significant increase in meprin-β.

"When we expose human neurons to beta-amyloid, we also observe an increase in meprin-β. This provides an experimental link between one of the hallmarks of Alzheimer's disease and the alteration we have found in patient samples," explains Sergio Escamilla, first author of the study.

Taken together, the findings point to a possible relationship between beta-amyloid accumulation and increased meprin-β levels. The authors suggest that this protein could be involved in processes related to the processing of amyloid precursor protein (APP), although they note that further studies will be needed to determine its potential use as an indicator of the disease.

The study involved researchers from the University Medical Center Mainz (Germany), the University of Barcelona and the University of Gothenburg (Sweden). Valero's team is also part of the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED) and the Institute for Health and Biomedical Research of Alicante (ISABIAL).

Publication details

Sergio Escamilla et al, Meprin-β levels are increased in the brain and the cerebrospinal fluid of Alzheimer's disease patients, Alzheimer's Research & Therapy (2026). DOI: 10.1186/s13195-026-02092-7

Journal information: Alzheimer's Research & Therapy

Key medical concepts

Alzheimer's DiseaseAmyloid beta-Peptides

Clinical categories

Neurology Provided by Miguel Hernandez University of Elche Who's behind this story?

Swati Mestri

Swati Mestri holds a bachelor's degree in Electronics Engineering and has worked as a content editor since 2019. She has experience editing research documents across technology, health care, and materials science, and has a particular interest in technology and space. Full profile →

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