Targeting microglia-mediated excessive synaptic elimination in Alzheimer's Disease (R-11610)

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. Notably, neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have been associated with excessive microglial synaptic pruning, resulting in a global loss in synaptic density, featured by a gradual cognitive impairment. Interestingly, our preliminary data show that DISC1 expression in microglia is key in maintaining physiological levels of synaptic pruning, potentially via inhibiting phosphodiesterase (PDE) activity. Moreover, while certain mutations in DISC1 are known to cause cognitive impairment in rodents, PDE inhibition has repetitively been shown to improve cognition and is predicted to hamper synaptic pruning. As such, we postulate that, in AD, impaired DISC1 function induces cognitive decline through PDE-mediated excessive synaptic pruning. Accordingly, our goal is to normalize PDE function to combat the excessive pruning phenotype of microglia. This will prevent excessive synapse loss featured in AD.

Keywords:Neurology

Disciplines:Cognitive neuroscience