Research led by the Achucarro Basque Center for Neuroscience, the University of the Basque Country (UPV/EHU), and the Ikerbasque Foundation has revealed the mechanisms that keep the brain clean during neurodegenerative diseases.
When neurons die, their debris need to be quickly removed in order for the surrounding brain tissue to continue to function properly. Elimination of the neuron corpses, in a process called phagocytosis, is carried out by highly specialized cells in the brain called microglia. These small cells have many ramifications that are in constant motion and are specially equipped to detect and destroy any foreign element, including dead neurons. Or so it was thought until now.
This study, published in PLOS Biology, investigates, for the first time, the process of neuronal death and microglial phagocytosis in the diseased brain. To this end, scientists collected brain samples from epilepsy patients at University Hospital of Cruces and from epileptic mice.
It is known that during epilepsy-associated seizures, neurons die. However, contrary to what happens in the healthy brain, during epilepsy, microglia seem to be “blind” and unable to find the dead neurons and to destroy them. Their behavior is abnormal. Therefore, dead neurons cannot be eliminated and accumulate, spreading the damage to neighboring neurons and triggering an inflammatory response that worsens the brain injury.
This discovery opens a new avenue to explore therapies that could alleviate the effects of brain diseases. In fact, the research group that undertook these studies is currently developing drugs, hoping to boost this cleaning process – phagocytosis – and help in the treatment of epilepsy.
The study was led by Dr. Amanda Sierra, director of the Laboratory of Glial Cell Biology at the Achucarro Basque Center for Neuroscience. The experimental work was mainly carried out by Oihane Abiega, Sol Beccari, and Irune Diaz Aparicio. Other scientists from Achucarro and UPV/EHU, including Juan Manuel Encinas, Jorge Valero, Victor Sanchez-Zafra, and Inaki Paris, also contributed to the study
This international research effort was coordinated from the Basque Country, and scientists from CIC bioGUNE (Spain), the University of Bordeaux (France), the University of Southampton (UK), Laval University (Canada), and Baylor College of Medicine (USA) also took part.
This work was supported by grants from the Spanish Ministry of Economy and Competitiveness with FEDER funds to AS (BFU2012-32089 and RYC-2013-12817) and JME (SAF2012-40085 and RYC-2012-11137); and from the Basque Government (Saiotek S-PC 12UN014) and Ikerbasque start-up funds to AS and JME; the Natural Sciences and Engineering Research Council of Canada (NSERC;) (RGPIN-2014-05308) to MET; NIH Intellectual and Developmental Disabilities Research Grant (P30HD024064) and Dana Foundation and McKnight Endowment for Science Work grants to MMS; grants from NIH R01 NS, 39943 and 49427 to AEA; and T32 NS and 43124 to ALB, who is a recipient of an Epilepsy Foundation Postdoctoral Fellowship; and Medical Research Council (MR/K022687/1) to DGN. In addition, OA is recipient of a predoctoral fellowship from the Basque Government, IDA is recipient of a predoctoral fellowship from the University of the Basque Country EHU/UPV, and VSZ is recipient of a predoctoral fellowship from the Spanish Ministry of Economy and Competitiveness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have declared that no competing interests exist.
Article: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling, Abiega O, Beccari S, Diaz-Aparicio I, Nadjar A, Layé S, Leyrolle Q, et al., PLoS Biology, doi:10.1371/journal.pbio.1002466, published 26 May 2016.