A study led by Javier Sáez Valero at the Instituto de Neurociencias of the Universidad Miguel Hernández de Elche and the Consejo Superior de Investigaciones Científicas found elevated active meprin-β in the brains and cerebrospinal fluid of people with Alzheimer's disease. Meprin-β can act as a β-secretase and may help process the amyloid precursor protein. The increase was clearest in advanced stages of the disease, not at its beginning.
Published in Alzheimer's Research & Therapy, the study distinguishes between two forms of the protein that researchers often combine when measuring protein levels. The investigators examined immature meprin-β, which is inactive, and the mature, active form. In samples from the frontal cortex, the active form increased during the later Braak stages. Messenger RNA from the MEP1B gene rose during intermediate and advanced stages.
The study was conducted by Sergio Escamilla and colleagues from the Altered Molecular Mechanism in Alzheimer’s Disease and Dementia laboratory at the Institute for Neurosciences of UMH-CSIC.
The basic finding was an increase in the active form of the protein.
That puts meprin-β alongside BACE1 in research into how beta-amyloid is made. Alzheimer's disease involves the buildup of beta-amyloid in the brain. The peptide appears when enzymes process the amyloid precursor protein, or APP. The researchers say their findings point to meprin-β as another enzyme that may take part in that process.
The cerebrospinal fluid results may also have clinical value. The team found more active meprin-β in samples from people with Alzheimer's disease. Cerebrospinal fluid is collected through a lumbar puncture, giving researchers material to study molecules linked to processes in the nervous system. The team presents the protein as a possible indicator for further study, not a diagnostic tool. MedicalXpress also describes it as a candidate marker of the enzyme's relationship with beta-amyloid, not a validated clinical test.
Earlier work discussed by Alzheimer Forschung Initiative indicates that meprin-β can be selectively inhibited. Christoph Becker-Pauly’s team in Kiel developed a new inhibitor with support from the foundation. The enzyme could be a potential therapeutic target if future studies show that blocking it reduces beta-amyloid formation.
Experiments in animals and human cells added support to the link with beta-amyloid. In transgenic rats that develop pathology associated with beta-amyloid buildup, active meprin-β also increased in cerebrospinal fluid. The team then used human neurons made from induced pluripotent stem cells. When the researchers exposed those neurons to the beta-amyloid peptide Aβ42, meprin-β increased significantly.
This sequence links the change found in patient samples to one of the basic features of Alzheimer's pathology. It does not prove that meprin-β causes the disease or show that measuring the protein can diagnose patients. The findings point to a biological relationship that needs more testing.
The project involved researchers from the Centro Médico Universitario de Mainz in Germany, the Universidad de Barcelona, and the Universidad de Gotemburgo in Sweden. Sáez Valero's laboratory is also part of CIBERNED and ISABIAL. Funding came from the Fondo de Investigaciones Sanitarias, the European Regional Development Fund, the Instituto de Salud Carlos III, the Generalitat Valenciana, the Ministerio de Ciencia Novedad y Universidades, the Agencia Estatal de Investigación, and the Severo Ochoa programme.
The study's basic contribution is its precision: it identifies the active form of meprin-β in brain tissue and cerebrospinal fluid and reproduces the increase after human neurons were exposed to Aβ42. The findings make the enzyme a serious subject for Alzheimer's research, but they are not enough to create a test or treatment. Meprin-β may help explain part of the beta-amyloid pathway. Any clinical use will require targeted studies first.
