Enlisting the immune system to fight Alzheimer disease can take the form of immunization against Aβ, or other attempts to modulate the inflammatory response that plays a role in disease. In a paper out in the April 2 issue of the Journal of Neuroscience, Elizabeth Head and colleagues of the University of California at Irvine present results of a two and a half year study of immunization of aged beagles with fibrillar Aβ. The study suggests that while immunization of the dogs was very efficient at clearing of cortical amyloid, that did not translate into improvements in tests of learning and memory. The authors suggest that prevention of amyloid buildup may be a better way to affect cognition.
A second study shows that modulation of the immune response by infusing human umbilical cord blood cells into AD mice can result in clearance of amyloid from both the brain and the vascular system. That study, from Jun Tan and colleagues at the University of South Florida in Tampa, is published in the March 26 issue of Stem Cells and Development, where they show that the treatment seems to work by blocking the CD40-mediated inflammatory response and increasing Aβ phagocytosis by microglia.
In the vaccination study, Head and her colleagues compared eight- to 12-year-old beagles, nine of which got a fibrillar Aβ1-42 vaccine monthly for two years, and 11 of which did not. The investigators saw a decline in soluble and insoluble Aβ peptides in the brain of immunized animals, but levels of soluble oligomers remained unchanged. They found no lessening of cognitive decline by most measures of learning, spatial attention, or spatial learning. They did see maintenance of prefrontal-dependent learning in a reversal trial. “One of the simplest interpretations of these data are [sic] that reducing preexisting brain Aβ is insufficient to restore neuronal and cognitive functions,” the authors write. They speculate that the one reason for the lack of improvement could be that the treatment did not affect levels of oligomers.
“The limited functional benefit suggests that prevention of Aβ accumulation by initiating treatment in middle-aged animals may be more efficacious as has been suggested in transgenic mouse models,” they conclude. However, questions remain about how faithfully the dogs, who accumulate diffuse amyloid plaques during aging, reflect Alzheimer disease as it manifests in people (see comment below by David Morgan, University of South Florida).
A second approach to immune modulation is presented by Tan, with University of South Florida coauthor Paul Sanberg, and Terrence Town of the Cedars-Sinai Medical Center in Los Angeles. First authors William Nikolic and Huayan Hou led the study, which involved infusing human umbilical cord blood cells (HUCBCs) into either PS/APP or Tg2576 mouse models for AD. In both cases, they saw a reduction of brain Aβ levels, amyloid plaques, and, in the Tg2576, a reduction in vascular amyloid deposits, along with a drop in inflammatory markers around plaques. With no behavioral data, it is unknown if the changes in pathology translate to cognitive improvements.
How does cord blood have its effect? The investigators provide evidence that the infusion leads to suppression of the CD40-CD40L pathway, a proinflammatory signaling pathway that they showed contributes to amyloid accumulation (see ARF related news story). CD40 is an accessory molecule on microglia and other immune cells that, when activated by its ligand CD40L, stimulates an inflammatory response. In microglia, CD40 stimulation promotes a proinflammatory response to Aβ and inhibits the Aβ phagocytosis. The researchers showed that infusion of cord blood cells led to an inhibition of the CD40-CD40L pathway in AD mice, associated with diminished blood levels of soluble CD40L (sCD40L). Serum Aβ levels were increased, indicating brain-to-blood efflux, which correlated with lowered brain Aβ. The mice also showed a shift in their blood cytokines from a proinflammatory to anti-inflammatory profile, and microglia from the treated mice showed enhanced uptake of Aβ in vitro. The effect of cord blood cells on microglia did not appear to be due to peripheral cells entering the brain, but rather was caused by a soluble factor that could be found in serum from treated mice. Finally, the in vivo anti-inflammatory and Aβ-mobilizing effects depended on CD40, since the infusion had no effect on inflammatory markers or serum Aβ in PS/APP mice lacking CD40.
“We propose that infused HUCBCs exert their effect on reducing cerebral amyloidosis by causing the host to secrete a soluble factor that acts by reducing sCD40L-CD40 interaction on microglia, which then promotes microglial clearance of Aβ,” the authors write. “Taken together, our results provide the basis for a novel immunomodulatory strategy for AD using HUCBCs,” they conclude. HUCBCs have shown promise in preclinical models of neuroinflammatory diseases, including stroke (see ARF related news story) and one previous study in AD mice (Ende et al., 2001 and see review by El-Badri et al., 2006), but whether all these effects are due to immunomodulation or other beneficial actions of the cells remains to be seen.—Pat McCaffrey