9 December 2005. The plaques and tangles of Alzheimer disease trigger an inflammatory response in microglia and astrocytes that reside in the brain, but whether and how cells of the peripheral immune system get into the act has been an open question. Understanding the interplay between brain and the immune system became a key issue after the Aβ vaccine trial was halted due to several cases of meningoencephalitis, which was subsequently blamed on the infiltration of inflammatory T cells into the brains of some patients.
Now, Mathias Jucker and colleagues at the University of Tuebingen, Germany, with collaborators in Switzerland, report that AD mice have significantly more peripherally derived immune cells in brain tissue than do control littermates. By transplanting APP-transgenic mice with bone marrow from donors expressing green fluorescent protein, the researchers distinguished bone marrow-derived hematopoietic cells from resident brain tissue. As they report in a November 30 paper in the Journal of Neuroscience, Jucker and colleagues found greater numbers of green T cells and macrophages in the brains of plaque-bearing mice compared to young, plaque-free transgenic mice or wild-type littermates. Previous work in mice has not detected T cell infiltration, whereas this is commonly seen in humans with AD.
When searching the brain for immune invaders, telling the new macrophage arrivals apart from resident brain microglia can be a challenge. The technique of bone marrow transplantation using hematopoietic cells from mice who express GFP was previously used by Finnish researchers, who showed that bone marrow-derived cells with an amoeboid morphology infiltrated the brain and surrounded plaques (Malm et al., 2004).
The new work, led by first author Anna Stalder, takes the technique a bit further, transplanting transgenic APP23 mice and control littermates at different ages from 4 months to 20 months, and analyzing brains before and after plaque deposition. Using immunohistochemistry to visualize GFP in brain sections, the researchers found that APP23 mice with plaques had higher GFP staining than did mice without plaques, and contained between 53 and 85 percent more GFP-positive cells in the neocortex, an area with high amyloid load. There was a trend towards increasing cell number with higher plaque load or cerebral amyloid accumulation, but this was not statistically significant. GFP-positive cell numbers were not elevated in young transgenic mice without amyloid plaques. All of the GFP-positive cells also expressed the hematopoietic marker CD45, but no endothelial, neuronal, or astrocytic markers. By confocal microscopy or EM morphology studies, 31 percent of the cells were identified as T cells, and up to 23 percent were macrophages.
Two puzzling results remain unexplained. First, while the invading amoeboid cells in the neocortex were mainly associated with plaques, not all plaques were equally visited. Consistently, only 20 percent of plaques had cells surrounding them, regardless of the age of the mice or extent of amyloid. It is not clear if a subset of plaques is fundamentally different and able to attract immune cells, or if all plaques attract immune cells at a particular time during their formation. The authors speculate that some early stage in plaque formation could be particularly toxic and/or attractive to immune cells.
Second, the reason why the cells move in, and what they do once there, remains a bit of a mystery. The researchers found no evidence that the macrophages were phagocytosing amyloid or that the T cells were kindling inflammation. But the ability of peripheral cells to freely enter the AD brain suggests that the cells might be put to use as little Trojan horses. “Harnessed with an amyloid-degrading enzyme or an immune modulator, autologous bone marrow-derived cells may offer a potent, targeted therapeutic strategy of clearing amyloid deposition and/or reducing amyloid-associated neurodegeneration,” the authors propose.—Pat McCaffrey.
Stalder AK, Ermini F, Bondolfi L, Krenger W, Burbach GJ, Deller T, Coomaraswamy J, Staufenbiel M, Landmann R, Jucker M. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci. 2005 Nov 30;25(48):11125-32. Abstract