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Protein implicated in Alzheimer’s Disease contributes to synapses normal development early in life, and its decline in aging

The function of the brain is regulated by synapses that establish the communication between neurons. Now, a new study led by Luísa Lopes, group leader at the Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal) and Paula Pousinha, researcher at the Université Côte d’Azur (IPMC, CNRS, France), and published in the scientific journal Aging Cell* discovered a double function for a protein implicated in Alzheimer’s Disease that regulates the activity of neuronal synapses in early life and aging.

The communication between neurons at the synapses can be carried out by the action of neurotransmitters, molecules that are released from one neuron and captured by receptors in the other. Amyloid precursor protein (APP), that is linked to Alzheimer’s Disease (AD), is known to regulate the activity of receptors that respond to a neurotransmitter called glutamate, and are critical for the development of a specific type of synapses – the glutamatergic synapses. This type of synapses is the most common in the hippocampus, an area of the brain particularly important for memory, and the region that the researchers studied in this work.

“Using mice as a model organism, we found that APP acts in two distinct ways dependent of the life stage. In infants, APP is present in its integral format and interacts with the receptors and changes its synaptic activity, likely contributing to their maturation and normal function. In aged mice, the same APP is processed in smaller fragments, like if it was chopped by a cellular butcher, that affect negatively the function of the receptors, and consequently the function of the synapses”, explains Luísa Lopes, co-leader of the study. “What was interesting for us is that we found a similar pattern in the APP fragments in the brain of elderly patients, which could indicate that this same processing of APP is also involved in the synaptic dysfunction in humans”, says Joana Saraiva, first author of the study and PhD student in Luísa Lopes laboratory.

“In fact, the mechanism that we found can be particularly relevant in the context of Alzheimer’s Disease. Although the APP protein is present in all brains, in Alzheimer’s Disease there is a pathological accumulation of the APP-derived fragments and the synaptic dysfunction that we observed in aging can be even more relevant in this disease. More importantly, this mechanism may explain why some mutations found in APP that reduce its chopping seem to protect patients from Alzheimer’s Disease. Also, this might explain why some drugs that normalize the function of the receptors targeted by APP are somewhat effective treatments in Alzheimer’s Disease”, adds Paula Pousinha, co-leader of the study, and an iMM alumni.

These findings show that is important to keep this protein under tight control. In early life APP is important for a healthy development, and in aging APP is contributing for brain function decline by a different mechanism. Understanding these mechanisms is important to define strategies to modulate this protein in the future, trying to act on its negative impacts on the aged brain and in Alzheimer’s Disease.

This work was developed at iMM in collaboration with the Université Côte d’Azur, Centre National de la Recherche Scientifique, France, and researchers from the University of Kaiserslautern, Germany, and the Ludwig-Maximilians-Universität München, Germany. This work was funded by Fundação para a Ciência, Santa Casa da Misericórdia, Ministère de la Recherche, de l’Enseignement Supérieur et de l’Innovation, and Forschung Initative.

*Joana Rajão-Saraiva, Jade Dunot, Aurore Ribera, Mariana Temido-Ferreira, Joana E. Coelho, Svenja König, Sébastien Moreno, Francisco J. Enguita, Michael Willem, Stefan Kins, Hélène Marie, Luísa V. Lopes* and Paula A. Pousinha*. Age-dependent NMDA receptor function is regulated by the Amyloid Precursor Protein. Aging Cell. 2023.