Bay-41 acts on sGC in microglia to reduce plaque load in Alzheimer’s disease mice independently of Clec7A

Alzheimer’s Disease is characterized by a pathological accumulation of amyloid beta driving neuronal loss. cGMP is a multitarget molecule that regulates many processes in the brain. Its production is initiated by the binding of Nitric Oxide (NO) to its receptor Soluble Guanylate Cyclase (sGC). However, in the context of AD, NO can act like a double-edged sword and drive Aß plaque clearing “Disease Associated Microglia” (DAM) into a harmful proinflammatory state through reactive oxygen species (ROS) mediated damage. Therefore, a carefully tailored DAM phenotype is required to limit AD progression.

The research focus is analyzing the state of microglia and DAM markers expression after chronic sGC stimulation in Alzheimer’s disease mice model 5xFAD.

The brain sections (50µm) which will be used in this study were already collected from WT, 5xFAD+Vehicle, 5xFAD+sGC mice that were treated with sGC stimulator or vehicle pellets over 10 months. We evaluated the expression and the localization of Clec7a and CD68 molecule with Aß plaques and microglia cells by Free-Floating Immunohistochemistry. Imaging data was acquired by confocal microscopy and analyzed by 3D reconstruction using Imaris software.

Here we show that Bay-41 acts downstream of NO leading to a transcriptional signature in DAM which reduces plaque load in a mice model of Alzheimer’s disease.