NMDA receptors and Alzheimer’s disease

A new study reveals the distribution of NMDA receptors, essential for memory, in brains with Alzheimer’s disease. The research has been carried out on human brains of deceased people.

The study is the work of a team from the Institute of Neurosciences (IN), a joint center of the Higher Council for Scientific Research (CSIC) and the Miguel Hernández University of Elche (UMH), in Spain.

The authors of the work have developed a method that allows us to precisely analyze how NMDA receptors, a type of receptors in neuronal synapses that are essential for neuronal plasticity, learning and the memory.

The results of the study reveal that, compared to healthy people, individuals with Alzheimer’s have a decrease in NMDA receptors in synapses and an increase in extrasynaptic membranes. This pioneering method opens new doors to search for more effective treatments to combat the disease.

Alzheimer’s disease is characterized by progressive memory loss and affects communication between neurons. This process depends largely on synapses, where NMDA receptors play a critical role in learning and memory. “Most NMDA receptors are found in synapses, where they enhance neuronal connections. However, those located outside the synapse are more related to toxicity and cell death processes, which can contribute to the progression of the disease,” explains Inmaculada Cuchillo Ibáñez, from the Institute of Neurosciences and co-author of the study.

The research team, which is part of the Network Biomedical Research Center for Neurodegenerative Diseases (CIBERNED) and the Alicante Health and Biomedical Research Institute (ISABIAL), analyzed post-mortem human brain samples that included both healthy individuals and patients in different stages of neurodegeneration. The results show a different distribution of NMDA receptors in the cortex of patients with Alzheimer’s disease, where the number of NMDA receptors in synapses is significantly reduced, while in extrasynapses there is an increase compared to healthy individuals. This imbalance would indicate that the activity related to neuronal toxicity would be favored in Alzheimer’s disease, with respect to the main function of synaptic transmission, probably contributing to the progression of the disease.

Neurons generated from stem cells of a patient with Alzheimer’s. They are visualized thanks to a green fluorescent marker. The nuclei are displayed in blue. (Image: IN / CSIC / UMH)

A pioneering protocol

The main advance that the researchers have achieved is the optimization of a cell fractionation protocol, which allows synaptic membranes to be isolated from extrasynaptic ones, something that had not been previously done in frozen post-mortem human brains. “Other studies had measured the total levels of NMDA receptors in the human brain, but did not differentiate between those located in synapses and those located in extrasynapses. We have adapted a protocol designed for fresh mouse brains, to be able to apply it to human samples, achieving this crucial separation,” highlights Sergio Escamilla, from the Institute of Neurosciences and co-author of the study.

The method is based on the use of detergents that dissolve fats from non-synaptic membranes, while the synaptic membranes, due to their high protein content, remain intact. Subsequently, by centrifugation, the membranes of both types are separated for analysis.

The findings of this work could open new avenues in the treatment of Alzheimer’s disease. “With this protocol we will be able to correctly distinguish whether specific reagents, such as modulators or blockers, have more affinity for synaptic or extrasynaptic receptors, and not just NMDA receptors, with the therapeutic consequences that this has,” says Cuchillo.

The study, which has had the collaboration of the laboratories directed by José Vicente Sánchez Mut and Isabel Pérez Otaño at the Institute of Neurosciences, also used transgenic mice to contrast the results obtained in humans. Although similar alterations were detected in NMDA receptors, the differences between species reinforce the need for studies in human tissue to better understand the disease.

With this pioneering protocol, researchers open new doors to explore the molecular bases of Alzheimer’s disease and search for more effective treatments to combat the disease. Along these lines, researcher Javier Sáez Valero, who directs the Altered Molecular Mechanisms in Alzheimer’s Disease and Other Dementia laboratory, highlights that this type of research is fundamental due to the importance of NMDA receptors in the current treatment of patients with the disease. Alzheimer’s, since memantine, one of the medications most used to treat this disease, is a blocker of these receptors.

The study is titled “Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer’s disease patients.” And it has been published in the academic journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. (Source: CSIC)