Microglia are a form of immune cell found in the central nervous system, responsible for a range of tasks including defense against pathogens and clearance of unwanted extracellular waste. Like all aspects of the immune system, their performance declines with age. Delivering young microglia to the aging brain has been proposed as a potential therapy by a number of research groups, and there has been some exploratory work in mice in recent years. Here researchers work in aged brain tissue sections rather than animal models, but show that introducing young microglia and the signals they produce enhances the removal of the amyloid-β deposits associated with Alzheimer's disease.
Alzheimer′s disease (AD) is the most prevalent neurodegenerative disorder and is pathologically defined by extracellular amyloid β (Aβ) deposition, neurofibrillary tangles, and neuroinflammation. Neuroimmune changes are tightly linked to the pathology of AD, as well as other neurodegenerative disorders. This link has been strengthened by recent discoveries of genes implicated in microglial function that are also risk factors for late onset AD. Interestingly, these newly identified risk factors may be functionally linked to microglial phagocytosis and Aβ clearance. Although microglia are well known for their phagocytic capacity and are found to surround amyloid plaques in mouse models of amyloidosis as well as in AD patients, their role in plaque clearance is still under debate.
One of the major limitations to study microglial contribution to amyloid plaque phagocytosis is the lack of suitable model systems. Major attempts to study microglial phagocytosis of Αβ come from studies using cultured microglial cells to which Aβ has been exogenously added. A key unresolved question is whether microglial dysfunction in AD is reversible and whether their phagocytic ability can be restored to limit amyloid accumulation. To this end, we developed a novel ex vivo model of amyloid plaque clearance by co-culturing young wild type (WT) brain slices together with brain slices from aged AD mice. We show that functional impairment of aged microglial cells in amyloid plaque-bearing tissue can be reversed through factors secreted by young microglia, resulting in increased amyloid plaque clearance and thus reduced amyloid plaque load. Our results suggest a role of microglia in reducing the amyloid burden and support development of therapeutic approaches modulating microglial activity.
Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.