Glial cytokines in Alzheimer's disease: review and pathogenic implications.
The roles of activated glia and of glial cytokines in the pathogenesis of Alzheimer's disease are reviewed. Interleukin-1 (IL-1), a microglia-derived acute phase cytokine, activates astrocytes and induces expression of the astrocyte-derived cytokine, S100 beta, which stimulates neurite growth (and thus has been implicated in neuritic plaque formation) and increases intracellular free calcium levels. Interleukin-1 also upregulates expression and processing of beta-amyloid precursor proteins (beta-APPs) (thus favoring beta-amyloid deposition) and induces expression of alpha 1-antichymotrypsin, thromboplastin, the complement protein C3, and apolipoprotein E, all of which are present in neuritic plaques. These cytokines, and the molecular and cellular events that they engender, form a complex of interactions that may be capable of self-propagation, leading to chronic overexpression of glial cytokines with neurodegenerative consequences. Self-propagation may be facilitated by means of several reinforcing feedback loops. beta-Amyloid, for instance, directly activates microglia, thus inducing further IL-1 production, and activates the complement system, which also leads to microglial activation with IL-1 expression. Self-propagation also could result when S100 beta-induced increases in intraneuronal free calcium levels lead to neuronal injury and death with consequent microglial activation. Such chronic, self-propagating, cytokine-mediated molecular and cellular reactions would explain the progressive neurodegeneration and dementia of Alzheimer's disease.
Mrak
R E
RE
Pathology and Laboratory Medicine Service, Department of Veterans' Affairs Medical Center, Little Rock, AR, USA.
Sheng
J G
JG
Griffin
W S
WS
D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis; D001253:Astrocytes / Q000737:chemistry; D016207:Cytokines / Q000032:analysis*; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D017628:Microglia / Q000737:chemistry* / Q000276:immunology*; D009418:S100 Proteins / Q000032:analysis; D016875:tau Proteins / Q000032:analysis
D016229:Amyloid beta-Peptides; D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D009418:S100 Proteins; D016875:tau Proteins