Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer's disease

• Published in: Alzheimer's research & therapy Vol. 13; no. 1; p. 8
• Main Authors: Pons, Vincent, Lévesque, Pascal, Plante, Marie-Michèle, Rivest, Serge
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.01.2021; BioMed Central; BMC
• Subjects: Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animal cognition; Animals; Antibodies; Binding sites; Bone marrow; Brain; Cognitive ability; Colony-stimulating factors (Physiology); Dementia; Development and progression; Disease Models, Animal; Gene expression; Genetic aspects; Health aspects; IL-34; Innate immunity; Kinases; Laboratories; mCSF; Membrane Glycoproteins - metabolism; Mice; Mice, Transgenic; Microglia; Mutation; Physiological aspects; Plaque, Amyloid; Prevention; Protein tyrosine kinase; Proteins; Receptor, Macrophage Colony-Stimulating Factor; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Receptors, Immunologic - metabolism; Sheep; TREM2; Tumor necrosis factor-TNF; β-Catenin; Canada; Cognitive decline; Innate immunity; β-Catenin; Amyloid; TREM2; mCSF; IL-34; Phagocytosis; Microglia
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-020-00747-7

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. Here, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice. Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APP . We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain. Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.