Microglia in neurodegenerative disease

Abstract

Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.

IRF8 is a transcriptional determinant for microglial motility

“…In addition to their role in maintaining CNS homeostasis, microglia play a central part in CNS pathologies [32][33][34], such as Alzheimer's disease, multiple sclerosis, and neuropathic pain. Therefore, our results may help to uncover potential targets for developing therapeutic treatments for neurodegenerative diseases.…”

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

“…Notably, microglia-derived MVs in the cerebrospinal fluid (CSF) have been recently identified as a novel biomarker of brain inflammation in humans. 30,31 The observation that typical proteins of EMVs, like flotilin, accumulate in the plaques of AD brain, 32 together with evidence that activated microglia constantly surround amyloid deposits, 33 prompted us to investigate whether EMVs may be involved in the spatiotemporal propagation of Ab pathology through the brain. Here we show that production of MVs is extremely high in patients with AD and that microglial MVs, either shed in vitro or isolated from the CSF of AD patients, promote generation of soluble neurotoxic Ab species, thereby acting as potent drivers of neuronal damage.…”

An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

“…Microglia are extremely versatile cells, which can acquire diverse phenotypes in response to specific trigger insults 46. In postmortem evidence in prionopathies, microglia cells seem to be able to clear apoptotic material but not PrP Sc , even after priming with lipopolysaccharide stimulation 47.…”