Abstract
Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid‐beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2‐photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post‐challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid‐beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.
Highlights
The brain has been conceived as an immune-privileged organ
Previous reports demonstrated that the peripheral administration of a single dose of lipopolysaccharide (LPS) ranging from systemic inflammation (0.5–1 mg/kg) to septic shock dosages (5–10 mg/kg) causes an immune response in the central nervous system (CNS), characterized by neuroinflammatory changes (Semmler et al, 2005, 2007; Qin et al, 2007; Gyoneva et al, 2014), identifying that microglia are affected by systemic immune processes
Using in vivo 2PLSM, we sought to determine the microglial dynamics behind these changes
Summary
It is widely accepted that several factors including obesity, acute injuries, aging, and neurodegenerative disease can trigger a sustained immune response in the central nervous system (CNS) leading to neuronal dysfunction and demise by microglia activation and release of neuroinflammatory mediators (Lucin & Wyss-Coray, 2009; Villeda et al, 2014; Heneka et al, 2015). AD is characterized by the deposition of amyloid-b (Ab), the formation of neurofibrillary tangles and neuroinflammation (Heneka et al, 2014). The initiation of the inflammatory response by microglia involves the multiprotein complexes termed “inflammasomes”. It has been shown that this process is highly dependent on the NLRP3 inflammasome (Halle et al, 2008; Heneka et al, 2013).
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