A team from the Altered Molecular Mechanism in Alzheimer’s Disease and Dementia laboratory, led by Javier S\u00e1ez Valero, a researcher at the Institute for Neurosciences (IN), a joint centre of the Miguel Hern\u00e1ndez University of Elche (UMH) and the Spanish National Research Council (CSIC), has identified increased levels of the protein meprin-\u03b2 in the brain and cerebrospinal fluid of people with Alzheimer’s disease. The results, published in Alzheimer’s Research & Therapy, show that it is particularly the active form of this protein that is elevated, providing new evidence of its possible relationship with processes associated with beta-amyloid, one of the hallmarks of the disease.<\/p>\n
Alzheimer’s disease is characterised, 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 \u03b2-secretases, including meprin-\u03b2.<\/p>\n
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Until now, much of the attention has focused on BACE1 as a relevant \u03b2-secretase in Alzheimer’s disease. Our work shows that there is another protein, meprin-\u03b2, whose active form is increased in the brain and cerebrospinal fluid of people with this disease.”<\/p>\n
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Javier S\u00e1ez Valero, study’s principal investigator<\/p>\n
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A protein in two forms<\/p>\n
Meprin-\u03b2 is an enzyme that can exist in different forms. To investigate what happens during Alzheimer’s disease, the researchers analysed its immature, still inactive form separately from its mature, active form.<\/p>\n
The team studied samples of the frontal cortex from patients 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.<\/p>\n
The results showed that the active form of meprin-\u03b2 increases in the more advanced stages of the disease, corresponding to the 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, the gene that contains the instructions for producing this protein, at intermediate and advanced stages.<\/p>\n
The team also analysed cerebrospinal fluid samples and detected increased levels of the active form of meprin-\u03b2 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 analyse molecules related to processes occurring in the nervous system<\/a>. “Finding increased levels of the active form of meprin-\u03b2 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 Javier S\u00e1ez Valero.<\/p>\n The relationship with beta-amyloid<\/p>\n To investigate whether the increase in meprin-\u03b2 could be related to beta-amyloid accumulation, the team analysed cerebrospinal fluid from transgenic rats that develop pathology associated with beta-amyloid accumulation. They also observed an increase in the active form of meprin-\u03b2 in these animals.<\/p>\n The researchers then used human neurons derived from induced pluripotent stem cells<\/a> (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 A\u03b242, the researchers observed a significant increase in meprin-\u03b2.<\/p>\n “When we expose human neurons to beta-amyloid, we also observe an increase in meprin-\u03b2. 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.<\/p>\n Taken together, the findings point to a possible relationship between beta-amyloid accumulation and increased meprin-\u03b2 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.<\/p>\n The study involved researchers from the University Medical Center Mainz (Germany), the University of Barcelona and the University of Gothenburg (Sweden). Javier S\u00e1ez 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).<\/p>\n This work was made possible thanks to funding from the Fondo de Investigaciones Sanitarias (FIS), the European Regional Development Fund (ERDF “Investing in your future”) of the European Union, the CIBERNED network of the Carlos III Health Institute, the CIAICO programme of the Direcci\u00f3 General de Ci\u00e8ncia i Investigaci\u00f3 of the Generalitat Valenciana, the Ministry of Science, Innovation and Universities, the State Research Agency and the Severo Ochoa Programme for Centres of Excellence.<\/p>\n Source:<\/p>\n Miguel Hern\u00e1ndez University of Elche (UMH)<\/a><\/p>\n Journal reference:<\/p>\n