Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease

Abstract Neuroinflammation is considered one of the cardinal features of Alzheimer’s disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the CNS, to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis. In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type. As such, several groups have targeted the peripheral immune system to modulate chronic neuroinflammation. In this review, we focus on the interplay of immunomodulating factors and cell types that are being investigated as possible therapeutic targets for the treatment or prevention of AD

Cranial irradiation acutely and persistently impairs injury-induced microglial proliferation

Microglia, the resident immune cells of the central nervous system (CNS), play multiple roles in maintaining CNS homeostasis and mediating tissue repair, including proliferating in response to brain injury and disease. Cranial irradiation (CI), used for the treatment of brain tumors, has a long-lasting anti-proliferative effect on a number of cell types in the brain, including oligodendrocyte progenitor and neural progenitor cells; however, the effect of CI on CNS-resident microglial proliferation is not well characterized. Using a sterile cortical needle stab injury model in mice, we found that the ability of CNS-resident microglia to proliferate in response to injury was impaired by prior CI, in a dose-dependent manner, and was nearly abolished by a 20 ​Gy dose. Similarly, in a metastatic tumor model, prior CI (20 ​Gy) reduced microglial proliferation in response to tumor growth. The effect of irradiation was long-lasting; 20 ​Gy CI 6 months prior to stab injury significantly impaired microglial proliferation. We also investigated how stab and/or irradiation impacted levels of P2Y12R, CD68, CSF1, IL-34 and CSF1R, factors involved in the brain’s normal response to injury. P2Y12R, CD68, CSF1, and IL-34 expression were altered by stab similarly in irradiated mice and controls; however, CSF1R was differentially affected. qRT-PCR and flow cytometry analyses demonstrated that CI reduced overall Csf1r mRNA levels and microglial specific CSF1R protein expression, respectively. Interestingly, Csf1r mRNA levels increased after injury in unirradiated controls; however, Csf1r levels were persistently decreased in irradiated mice, and did not increase in response to stab. Together, our data demonstrate that CI leads to a significant and lasting impairment of microglial proliferation, possibly through a CSF1R-mediated mechanism