Out-of-control microglia cause cognitive deficits through excessive synaptic elimination in Alzheimer's Disease (R-10227)

Microglia, the resident immune cells of the brain, are involved in maintaining proper brain functioning and cellular communication. Under physiological conditions, microglia apply synaptic pruning to eliminate redundant and weak synapses. Synaptic pruning is essential to shape and maintain an efficient neuronal network. In neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, microglial synaptic pruning is too excessive, resulting in a global loss in synaptic density, featured by a gradual cognitive impairment. A scaffolding protein has recently been shown to be highly expressed in adult microglia. Interestingly, our preliminary data show that it is involved in restricting synaptic pruning. In line, mutations in its gene cause cognitive impairment in rodents. Interestingly, the scaffolding protein functionally blocks phosphodiesterase (PDE) activity. Inhibition of PDE improves cognition and is predicted to hamper synaptic pruning. In healthy individuals, PDE is blocked to a certain degree by the protein. So when its function fails, PDE's are dysregulated. Our goal is to intervene and block PDE again to battle the cognitive decline featured in AD.

Keywords:Alzheimer, Cognition, Neurodegeneration

Disciplines:Cognitive neuroscience, Neurophysiology, Molecular physiology