Researchers have found a new microglial link between Aβ and neuroinflammation, two hallmarks of Alzheimer’s disease. It is a particular brand of inflammasome, a molecular machine that activates inflammatory cytokines in response to certain toxic signals. Silencing the inflammasome seems to uncouple Aβ from inflammation and reduce amyloid pathology in mouse models of AD, Michael Heneka and Eicke Latz of the University of Bonn, Germany, as well as Douglas Golenbock, University of Massachusetts Medical School, Worcester, report in the December 20 Nature. Genetically eliminating the complex prevented behavioral deficits in transgenic mice, likely by altering microglial activation. The authors surmised that the inflammasome might one day make a good therapeutic target to stave off AD. Heneka presented some of this work earlier this month on Alzforum (view full Webinar and Heneka's slide presentation).
“This [work] adds to the recent plethora of data linking inflammatory reactions and Alzheimer’s,” said Frank Heppner, Charité Universitaetsmedizin Berlin, Germany. “It’s yet another strong indication that the innate immune response is an important player [in disease], and that when specifically targeted, it can really make a difference in terms of manipulating AD pathology.”
Inflammasomes are microglial multiprotein complexes that promote the release of proinflammatory cytokines in response to pathogens or signs of cell damage. They contain members of the NOD-like receptor (NLR) protein family, which recognizes and binds ligands such as cholesterol, silica, or uric acid. The inflammasomes activate caspase-1, which then releases IL-1β and IL-18 to initiate an innate immune response. Golenbock’s group previously showed that inflammasomes containing the NLRP3 receptor recognize Aβ in cell culture (see Halle et al., 2008), stimulating IL-1β release. However, it was unknown if NLRP3-inflammasomes behave the same way in vivo, or whether eliminating NLRP3 could modulate AD.
To find out, Heneka and colleagues disabled NLRP3 inflammasome signaling in APP/PS1 mice by crossing them with NLRP3 or caspase-1 knockouts. They examined offspring at 16 months of age. Without functional inflammasome signaling, crosses performed better than APP/PS1 mice in the Morris water maze and in object recognition tests of memory. What’s more, long-term potentiation and synaptic spine density were normal in the crosses, whereas both faltered in age-matched APP/PS1 mice. APP/PS1/NLRP3-negative animals also deposited 70 percent less Aβ in the brain. Taken together, the results implied that reducing signaling from this particular inflammasome improved both behavioral and cognitive function in transgenic mice.
How does blocking this inflammasome reduce Aβ pathology? Switching off proinflammatory cytokines such as IL-1β probably allows microglia to adopt an M2 phenotype and resume amyloid clearance, said Heneka. Compared to microglia from APP/PS1 mice, those from NLRP3- or CASP1-negative animals gobbled twice the Aβ. Researchers are just recently coming to grips with different microglial phenotypes, with proinflammatory (M1) and anti-inflammatory (M2) being major demarcations (see ARF related news story). The authors offer “pretty convincing evidence that there was a change in the phenotype of these microglia,” said David Cribbs, University of California, Irvine. These data may translate to humans, write the paper’s authors, since postmortem tissue from sporadic and early-onset AD patients, as well as those with mild cognitive impairment, showed elevated caspase-1 compared with controls.
Inflammasome reduction could come with certain side effects, however, said Terrence Town, Cedars-Sinai Medical Center, Los Angeles, California. His team recently reported that the NLRP3 inflammasome is critically important for defense against salmonella (see Shimada et al., 2012). “Their findings are impressive, and show for the first time that the NLRP3 inflammasome plays a critical role in development of AD pathophysiology," he told Alzforum. "However, it’s quite possible that [inflammasome depletion] would render folks more susceptible to bacterial infection,” he said. “This would have to be looked at as a potential adverse event should this work move toward the clinic.”
Heneka told Alzforum that he will next explore the role of inflammation in the spread of Aβ or tau pathology. He also wants to examine the mechanisms that underlie phagocytic degradation of Aβ and search for compounds that quash inflammasome signaling. Already, Latz is screening a library of blood-brain barrier-penetrable compounds for ones that specifically disable NLRP3.—Gwyneth Dickey Zakaib
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