Low‐grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's‐like pathology

• Published in: Glia Vol. 72; no. 7; pp. 1340 - 1355
• Main Authors: Guerrero‐Carrasco, Monica, Targett, Imogen, Olmos‐Alonso, Adrian, Vargas‐Caballero, Mariana, Gomez‐Nicola, Diego
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2024; Wiley Subscription Services, Inc
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Brain - metabolism; Brain - pathology; Cytokines - metabolism; Disease Models, Animal; disease‐associated microglia; Female; In vivo methods and tests; Inflammation; Inflammation - metabolism; Inflammation - pathology; Inflammatory response; Lipopolysaccharides; Lipopolysaccharides - pharmacology; LPS; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Microglia - metabolism; Microglia - pathology; Neurodegenerative diseases; Neurological diseases; Pathology; Preconditioning; proliferation; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Sickness behavior; β-Amyloid; disease‐associated microglia; proliferation; Alzheimers disease; microglia; LPS
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24532

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low‐grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low‐grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)‐like pathology. Our results indicate that low‐grade systemic inflammation induces sub‐threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low‐grade LPS induce disease‐associated microglia. Finally, using an inducible model of AD‐like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low‐grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aβ accumulation and disease‐associated microglia. These results support the notion that episodic low‐grade systemic inflammation has the potential to influence the onset and severity of age‐related neurological disorders, such as AD. Main Points Systemic challenge with low dose LPS increases microglial proliferation without causing overt inflammation. Repeated challenges with low dose LPS during healthy life accelerate the onset of amyloidosis and increase Dectin‐1+ cells in AD‐like pathology.