Abstract
BackgroundUndoubtedly, neuroinflammation is a major contributor to Alzheimer’s disease (AD) progression. Neuroinflammation is characterized by the activity of brain resident glial cells, in particular microglia, but also by peripheral immune cells, which infiltrate the brain at certain stages of disease progression. The specific role of microglia in shaping AD pathology is still controversially discussed. Moreover, a possible role of microglia in the interaction and recruitment of peripheral immune cells has so far been completely ignored.MethodsWe ablated microglia cells in 12-month-old WT and APP-PS1 transgenic mice for 4 weeks using the CSF1R inhibitor PLX5622 and analyzed its consequences to AD pathology and in particular to peripheral immune cell infiltration.ResultsPLX5622 treatment successfully reduced microglia numbers. Interestingly, it uncovered a treatment-resistant macrophage population (Iba1+/TMEM119−). These cells strongly expressed the phagocytosis marker CD68 and the lymphocyte activation, homing, and adhesion molecule CD44, specifically at sites of amyloid-beta plaques in the brains of APP-PS1 mice. In consequence, ablation of microglia significantly raised the number of CD3+/CD8+ T-cells and reduced the expression of anti-inflammatory genes in the brains of APP-PS1 mice.ConclusionWe conclude that in neurodegenerative conditions, chronically activated microglia might limit CD3+/CD8+ T-cell recruitment to the brain and that local macrophages connect innate with adaptive immune responses. Investigating the role of peripheral immune cells, their interaction with microglia, and understanding the link between innate and adaptive immune responses in the brain might be a future directive in treating AD pathology.
Highlights
Neuroinflammation is a major contributor to Alzheimer’s disease (AD) progression
CSF1R inhibition with PLX5622 diminished microglia but revealed a PLX5622-resistant population in the brains of APP-PS1 mice To analyze the relevance of microglia in amyloid plaque pathology and central nervous system (CNS) inflammation, we ablated these cells for a total of 28 days using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in 12-months-old APP-PS1 mice and WT littermate controls (Fig. 1a)
The CSF1R is a cytokine receptor highly expressed on microglia and macrophages [54], and microglia survival in the adult brain strictly depends on CSF1R signaling [55]
Summary
Neuroinflammation is a major contributor to Alzheimer’s disease (AD) progression. The brains resident immune cells, are a key element in inflammatory processes of the central nervous system (CNS) and are mediating chronic neuroinflammation and aggravation of AD pathology (reviewed in [8, 10, 11]). Besides the creation of a disease-stage-specific pro- or anti-inflammatory environment, one of the main functions of microglia is to phagocytose and degrade dying cells, cellular debris, and toxic molecules (reviewed in [15]), as for example amyloid-beta along AD pathology While the initial immune response to amyloid-beta is described as beneficial because it counteracts plaque formation [19], chronically activated microglia stir disease progression through the secretion of pro-inflammatory cytokines and neurotoxic factors (reviewed in [20]). Microglia have multiple and extremely disease-stage-specific roles and functions in AD pathology
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