Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models

Abstract

Microglia are the primary immune cell of the brain and function to protect the central nervous system (CNS) from injury and invading pathogens. In the homeostatic brain, microglia serve to support neuronal health through synaptic pruning, promoting normal brain connectivity and development, and through release of neurotrophic factors, providing support for CNS integrity. However, recent evidence indicates that the homeostatic functioning of these cells is lost in neurodegenerative disease, including Alzheimer’s disease (AD), ultimately contributing to a chronic neuroinflammatory environment in the brain. Importantly, the development of compounds and genetic models to ablate the microglial compartment has emerged as effective tools to further our understanding of microglial function in AD. Use of these models has identified roles of microglia in several pathological facets of AD, including tau propagation, synaptic stripping, neuronal loss, and cognitive decline. Although culminating evidence utilizing these microglial ablation models reports an absence of CNS-endogenous and peripheral myeloid cell involvement in Aβ phagocytosis, recent data indicates that targeting microglia-evoked neuroinflammation in AD may be essential for potential therapeutics. Therefore, identifying altered signaling pathways in the microglia-devoid brain may assist with the development of effective inflammation-based therapies in AD.

Baicalin mitigates cognitive impairment and protects neurons from microglia‐mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF‐κB signaling pathway

“…Activated microglia are important mediators of Aβ‐induced neurotoxicity via the production of proinflammatory cytokines . To further evaluate whether BAI suppressed microglial activation in LPS/Aβ‐stimulated BV2 cells, we analyzed Iba‐1 protein expression levels using Western blot and immunofluorescence.…”

Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice

“…Our studies reveal the critical role of microglia in orchestrating postoperative neuroinflammation and memory loss, and a heretofore-unrecognized interplay between microglia and circulating monocytes. We thus posit that microglia could be targeted to lessen POCD, as they have been targeted to limit neurodegenerative forms of cognitive decline (23).…”

Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

“…Colony-stimulating factor 1 (CSF1) is thought to be essential in maintaining homeostasis in microglial populations (23). The CSF1 receptor (CSF1R) kinase inhibitor PLX5622 has been shown to deplete microglia with minimal effects on normal CNS function (24,25) and has been used to investigate the consequences of microglia depletion in several settings, including recently in a murine coronavirus model (26). Microglial depletion has not yet been studied in the context of flaviviral infection.…”