Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology.
Genetic and molecular studies have confirmed the central role of amyloid-beta production and fibrillation in the pathogenesis of Alzheimer's disease (AD). However, the pathological pathways from amyloid-beta peptide oligomerization to the major pathological hallmarks of AD, such as neurofibrillary tangles, inflammation and loss of cholinergic neurons, are largely unknown. The innate immunity defence system utilizes pattern recognition receptors to respond to a variety of danger- and pathogen-associated molecular structures. Amyloid-beta oligomers and fibrils and their cellular effects can activate the innate immunity defence and induce inflammatory and apoptotic responses in human brain. Amyloid-beta oligomers can interfere with many aspects of neuronal membrane functions and can evoke potassium (K+) efflux from neurons. A low K+ concentration is a potent activator for the NALP1 inflammasomes, which then stimulate caspase-1 to cleave the proforms of IL-1beta and IL-18 cytokines. Interestingly, recent observations have demonstrated that amyloid-beta fibrils can activate NALP3 inflammasomes Via the lysosomal damage in mouse microglia. We will review here the activation mechanisms of NALP inflammasomes in neurons and microglia and several downstream effects in brain demonstrating that toxic amyloid-beta oligomers and fibrils can light afire in inflammasomes and induce Alzheimer's pathology.
Salminen
Antero
A
Department of Neurology, Institute of Clinical Medicine, University of Kuopio, and Kuopio University Hospital, Kuopio, Finland. antero.salminen@uku.fi
Ojala
Johanna
J
Suuronen
Tiina
T
Kaarniranta
Kai
K
Kauppinen
Anu
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D017136:Ion Transport; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008959:Models, Neurological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D020836:Protein Structure, Quaternary
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D007375:Interleukin-1; D046912:Multiprotein Complexes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human; D011498:Protein Precursors; C043830:interleukin 1 precursor; D011188:Potassium
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