Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome.
Dario TejeraDilek MercanJuan M Sanchez-CaroMor HananDavid GreenbergHermona SoreqEicke LatzDouglas GolenbockMichael T HenekaPublished in: The EMBO journal (2019)
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.
Keyphrases
- inflammatory response
- cognitive decline
- nlrp inflammasome
- lps induced
- lipopolysaccharide induced
- mild cognitive impairment
- neuropathic pain
- toll like receptor
- immune response
- high resolution
- white matter
- resting state
- endothelial cells
- spinal cord
- oxidative stress
- spinal cord injury
- high speed
- cerebral ischemia
- single cell
- single molecule
- cognitive impairment
- high throughput
- stem cells
- functional connectivity
- skeletal muscle
- type diabetes
- traumatic brain injury
- metabolic syndrome
- multiple sclerosis
- mass spectrometry
- protein kinase
- high fat diet induced