8 June 2007. Results from a mouse model of chronic neuroinflammation suggest that fanning the flames of microglial activation can be beneficial in dealing with the amyloid buildup that occurs in Alzheimer disease.
M. Kerry O’Banion at the University of Rochester, New York, and colleagues show that long-term IL-1β expression in the hippocampus of AD mice reduces amyloid deposition, probably by stimulating microglia to clear amyloid-β (Aβ). The results appear in this month’s Journal of Clinical Investigation.
In the model, direct injection of a Cre-expression virus turned on an excision-activated IL-1β transgene in the hippocampus. The resulting localized and sustained IL-1β production caused a prolonged inflammation, complete with astrocyte and microglia activation. The researchers expected to see the plaque pathology get worse as a result of IL1-β being induced in this way in an APP/PS mouse. Instead, plaque number in the “inflamed” mice was lower, and insoluble Aβ levels reduced. The changes were accompanied by an increase in the number of activated microglia in close contact with plaques.
“These results indicate that neuroinflammatory processes in AD may at times represent an adaptive response and argue against the indiscriminate use of anti-inflammatory therapies in AD,” the authors write.
In an accompanying commentary, Cynthia Lemere of Harvard Medical School in Boston, Massachusetts, points out that while the potential beneficial effects of immune activation are of growing interest to AD researchers, the effects of inflammatory cytokines depend on context and time. The new mouse model provides a valuable tool to dissect the effects of IL-1β. Manipulating the immune system may be a potential therapeutic approach against AD, but more work is needed to understand the downstream effects of doing so, Lemere writes.—Pat McCaffrey.
Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O'banion MK. Sustained hippocampal IL-1beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest. 2007 Jun;117(6):1595-604. Abstract
Lemere CA. A beneficial role for IL-1beta in Alzheimer disease? J Clin Invest. 2007 Jun 1;117(6):1483-1485. Abstract