Researchers from the Institute for Neurosciences (IN), a collaborative effort between Miguel Hernández University of Elche (UMH) and the Spanish National Research Council (CSIC), have developed a groundbreaking cellular fractionation protocol that enables detailed analysis of NMDA receptor distribution in human postmortem brains. This innovative method allows scientists to distinguish between proteins located in synaptic membranes and those in extrasynaptic membranes, providing critical insights into Alzheimer’s disease.
The findings of this study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, highlight significant changes in NMDA receptors associated with Alzheimer’s disease. Compared to healthy individuals, patients with Alzheimer’s show a marked decrease in NMDA receptors at synapses and an increase in those located in extrasynaptic membranes.
Alzheimer’s disease is characterized by progressive memory loss and impaired communication between neurons, processes that heavily rely on synaptic function. NMDA receptors are vital for synaptic transmission and play a crucial role in learning and memory. “While most NMDA receptors are found in synapses, enhancing neuronal connections, those outside the synapse are linked to toxicity and cell death, potentially accelerating disease progression,” explains Inmaculada Cuchillo Ibáñez, a leading researcher at the Altered Molecular Mechanism in Alzheimer’s Disease and Dementia laboratory.
The research team analyzed postmortem brain samples from both healthy individuals and patients at various stages of neurodegeneration. They found a significant reduction in synaptic NMDA receptors in the cortical areas of Alzheimer’s patients, coupled with an increase in extrasynaptic receptors. This shift suggests a favoring of toxic neuronal activity over normal synaptic transmission, likely contributing to the advancement of the disease.
The researchers achieved a significant breakthrough by optimizing a cellular fractionation protocol that separates synaptic from extrasynaptic membranes in frozen human postmortem brains. “Previous studies have only measured total NMDA receptor levels without differentiating their locations. We adapted a protocol initially designed for fresh mouse brains to human samples, enabling this crucial separation,” said Sergio Escamilla, the study’s first author.
This method employs detergents that dissolve lipids in non-synaptic membranes, allowing synaptic membranes—characterized by their high protein content—to remain intact. Centrifugation is then used to separate the two types of membranes for further analysis.
The implications of this research are significant for developing new therapeutic strategies for Alzheimer’s disease. “Our protocol enables us to determine the affinity of specific agents, such as modulators or blockers, for synaptic versus extrasynaptic receptors, which is critical for therapeutic development,” notes Cuchillo.
The study also collaborated with the laboratories of José Vicente Sánchez Mut and Isabel Pérez Otaño at IN UMH-CSIC, utilizing transgenic mice to validate the findings observed in human tissues. While similar alterations in NMDA receptors were identified, the differences between species underscore the necessity of human tissue studies for a deeper understanding of the disease.
Javier Sáez Valero, head of the Altered Molecular Mechanism in Alzheimer’s Disease and Dementia laboratory, emphasizes the importance of this research, particularly given the role of NMDA receptors in current Alzheimer’s treatments. Memantine, a widely used drug for the condition, functions as an NMDA receptor blocker.
This research was supported by the Health Research Fund, co-funded by the European Regional Development Fund (ERDF), the Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), the Carlos III Health Institute, and the Directorate General for Science and Research of the Generalitat Valenciana.
With this pioneering protocol, researchers are poised to further explore the molecular underpinnings of Alzheimer’s disease and advance the search for effective treatments.
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