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

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 inflammati...

Full description

Saved in:
Bibliographic Details
Published in:Glia 2024-07, Vol.72 (7), p.1340-1355
Main Authors: Guerrero‐Carrasco, Monica, Targett, Imogen, Olmos‐Alonso, Adrian, Vargas‐Caballero, Mariana, Gomez‐Nicola, Diego
Format: Article
Language:English
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
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0894-1491
1098-1136
1098-1136
DOI:10.1002/glia.24532