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

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Systemic inflammation, often induced by lipopolysaccharide (LPS), triggers central nervous system (CNS) inflammation and sickness behavior.
• Existing research primarily uses high-grade systemic inflammation models, unlike the common low-grade inflammatory events in humans.

Purpose of the Study:

• To investigate the effects of low-grade systemic inflammation during early life on Alzheimer's disease (AD)-like pathology.
• To determine if early-life inflammation pre-conditions the brain for AD onset and severity later in life.

Main Methods:

• Mice were subjected to repeated low-grade systemic LPS challenges during early life.
• An inducible model of AD-like pathology (Line 102 mice) was used to assess the impact of prior inflammation.
• Microglial proliferation, cytokine levels, and amyloid-beta (Aβ) accumulation were analyzed.

Main Results:

• Low-grade systemic inflammation induced sub-threshold brain inflammation and microglial proliferation via the CSF1R pathway.
• Repeated low-grade LPS challenges led to the development of disease-associated microglia.
• Preconditioning with low-grade inflammation exacerbated Aβ accumulation and disease-associated microglia in the AD model.

Conclusions:

• Episodic low-grade systemic inflammation can influence the onset and severity of age-related neurological disorders, including Alzheimer's disease.
• Early-life inflammatory events may represent a critical window for AD pathogenesis.