In this issue, and demonstrate that replacing resident microglia with peripherally derived myeloid cells, remarkably, does not impact pathology in Alzheimer’s disease (AD) mouse models.
Increasing evidence suggests a link between neuroinflammation and amyloid pathology in AD. Inflammatory myeloid cells accumulate around amyloid plaques in the human AD brain and in AD mouse models. However, these cells fail to mount a productive phagocytic response to effectively clear amyloid from the brain. It has been proposed that microglia become dysfunctional because of age or disease state and that perhaps replacing these cells with a more competent, blood-derived myeloid cell population would result in amyloid clearance and ameliorate pathology. Indeed, a variety of studies have suggested that infiltration and engraftment of peripheral myeloid cells in the CNS could alter AD-like pathologies.
The authors cross multiple AD mouse models to their CD11b-HSVTK model of microglial depletion. In untreated mice (top panels) myeloid cells cluster around plaques. After 10–14 days of intraventricular gancyclovir administration, microglia are largely eliminated from the brain. After 2–12 weeks of recovery after gancyclovir administration, myeloid cells repopulate the CNS, but these cells do not associate with amyloid deposits. There is no change in amyloid deposition at any stage compared with nondepleted mice. To determine the origin of repopulating myeloid cells, the authors use labeled parabiotic pairs (botton panels) and demonstrate that repopulation after gancyclovir administration occurs via infiltration of peripherally derived myeloid cells.
The authors cross multiple AD mouse models to their CD11b-HSVTK model of microglial depletion. In untreated mice (top panels) myeloid cells cluster around plaques. After 10–14 days of intraventricular gancyclovir administration, microglia are largely eliminated from the brain. After 2–12 weeks of recovery after gancyclovir administration, myeloid cells repopulate the CNS, but these cells do not associate with amyloid deposits. There is no change in amyloid deposition at any stage compared with nondepleted mice. To determine the origin of repopulating myeloid cells, the authors use labeled parabiotic pairs (botton panels) and demonstrate that repopulation after gancyclovir administration occurs via infiltration of peripherally derived myeloid cells.
In the current issue, both investigators use mouse models in which herpes simplex virus thymidine kinase (HSVTK) is expressed under the control of the CD11b promoter. HSVTK can modify ganciclovir into a toxic product. So, upon intracerebroventricular administration of ganciclovir, CD11b-expressing resident microglia were eliminated from their AD mouse models. Prokop et al. performed parabiosis experiments to demonstrate that 28 days after the withdrawal of ganciclovir administration, peripherally derived myeloid cells infiltrate and repopulate the CNS. Surprisingly, these peripherally derived cells failed to home to amyloid plaques, and the authors found no resultant change in amyloid pathology. Varvel et al. reported similar results two weeks after repopulation by peripheral myeloid cells, but after longer-term engraftment in the CNS, the peripherally derived cells do eventually cluster around amyloid deposits. Remarkably, despite the near total replacement of resident microglia by peripherally derived myeloid cells, the authors found no significant change in amyloid deposition.
Together, these studies suggest that replacement of microglia by peripherally derived myeloid cells is not sufficient to enhance amyloid clearance and ameliorate AD pathology. Rather, it appears that the tissue microenvironment plays a key role in regulating myeloid cell function as it relates to amyloid clearance regardless of cell ontogeny. Despite these findings, it is still possible that recruitment of specific myeloid cell subsets in AD could contribute to plaque clearance, as the global elimination of microglia that drove repopulation in these studies may not attract the same cells that enter the CNS in the context of AD. Nevertheless, the findings in these studies suggest that largescale replacement of microglia with peripheral myeloid cells in itself is unlikely to be an effective therapeutic strategy to promote amyloid clearance in AD patients.
