Microglia Marker Proteins

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 Microglia Marker Proteins Background

Microglia are the innate immune cells of the brain. Although first postulated by Pio del Rio Hortega around 1920 to be mesodermally-derived (unlike neurons, astrocytes and oligodendrocytes), it was not until the 1990s that microglia were established as descendants of the myelomonocytic lineage and thus likely of hemangioblastic origin. Unlike adult peripheral macrophages, microglia are derived from the primitive yolk sac (Myb-independent) and enter the embryonic neuroepithelium around the time neurulation completion as amoeboid in morphology (~8.5 days post conception; dpc). Interestingly, newly positioned amoeboid microglia arrive in the neuroectoderm before it even becomes vascularized. Once the newly established amoeboid microglia enter the brain, they undergo proliferation, shift their morphologic phenotype to a ramified state and diffuse out to essentially cover the entire brain in a spatially delineated, grid-like pattern. Constituting approximately 2.5-10% of all brain cells (5-20% of neuroglia), microglia number one to every neuron, which does suggest a vital role in neuronal development and homeostasis. Recent evidence suggests microglia facilitate removal of apoptotic neurons and strip dendrites of weakly connected synapses during brain development.

In the adult brain, ramified microglia have the ability to react to any number of stimuli in a matter of minutes, mounting an immune response. Termed the “garbage men” of the brain, microglia are professional and highly efficient phagocytes, utilizing several methods for engulfing debris.

A caveat seems to arise, however, in their ability to degrade Aβ. Although microglia make use of a plethora of phagocytic receptors for Aβ uptake, the majority of Aβ (including both fibrillar and soluble forms) goes undigested and is released from the cell. Chung et al. (1999) found that microglia phagocytized fAβ within three days. However, after three days, intact Aβ was slowly released. In contrast, sAβ was internalized and then immediately released without much degradation. On the other hand, peripheral macrophages in culture can efficiently phagocytize and degrade fAβ from the N terminus. These findings match early interpretations of the role of microglia in plaque homeostasis as Aβ producers. The explanation for this weakness of microglia-mediated Aβ phagocytosis may either reside in the inherent inactivity of some lysosomal enzymes or to decreased microglial lysosomal acidity. Primary murine microglia incubated with mannose-6- phosphate tagged lysosomal enzymes showed enhanced degradation of fAβ, while microglia activated by macrophage colony stimulating factor or IL-6 had increasingly acidified lysosomes, which resulted in increased fAβ digestion. A recent hypothesis has been put forward, however, that suggests microglia are recruited to the site of neuritic plaques to clear dead or dying neurons, not Aβ, much like they do in the developing brain.

Another plausible explanation for microglial inadequacies at clearing aggregated proteins is simply their age. Microglia, like all other cells in the body, have a predetermined lifespan and begin to senesce at older ages. At this point, they may begin to become dysfunctional and inappropriately activated to even the smallest stimuli. This inappropriate activation may be due to a process called “priming,” in which small stimuli essentially put the cell into a state of alert and any stimuli to follow, regardless of its intent, will result in an extremely robust response. Increased levels of human leukocyte antigen (HLA) DR on microglia from aged human brains is considered a marker for priming in the CNS, however this should be taken with caution as many resting microglia also express HLA-DR. Instead, microglial dystrophy, which involves any number of morphologic changes to microglia (i.e. deramification, beading or fusing), is a sign of microglial senescence and ultimately results in fragmentation of microglial cell bodies. Interestingly, Streit et al. (2009) also showed with human histopathology that fragmented microglia colocalize with neuronal NFT pathology and that dystrophic microglia precede the formation of neuronal degeneration. Combining molecular phenotype and cell morphology, Perry and colleagues determined that microglia are primed by ongoing pathology or age, which manifests as morphological changes and only after a second insult (such as peripheral infection) do the cells go through phenotypic switching to express markers of inflammation, such as IL-1β, IL-6 or TNFα.


Microglia and Huntington’s disease (HD)

Microglia have been long overlooked in HD; however, recent studies increasingly implicate their potential role in the disease. Coincident with selective neuronal loss in the cortex and striatum, reactive microglia are found in these regions in HD brains. Reactive gliosis also occurs in early stages of neuronal dysfunction in HD mouse models. Recently, a study demonstrated that, beginning at 2–4 weeks of age, microglia in the R6/2 mouse model show more ferritin immunostaining than their wild-type littermates. Ferritin accumulation is often indicative of cellular dysfunction and thought to contribute to pathology in various neurodegenerative diseases. These changes also progressed with disease severity. Microglia showed morphological changes, such as thickening and dystrophy of their processes, which began at 8–10 weeks of age. Brains from mid-stage HD patients also had increased ferritin immunostaining in microglia, many of which are dystrophic. A second study also showed that R6/2 brains have microglia with condensed nuclei and fragmentation of their processes at 14.5 weeks of age.

Abnormal microglia have also been described in the brains of pre-manifest HD patients. Positron emission tomography from HD patients also showed an increase in binding of 11C-(R)-PK11195, a surrogate marker for microglial activation in vivo, in the striatum and cortex that correlates to HD severity. Furthermore, microglial activation in brain regions required for cognitive function can predict disease onset. Although there is strong evidence demonstrating that microglia and their dysfunction may be an important contributor to HD pathogenesis, these previous studies are merely descriptive and do not establish a causal link between any of these abnormalities and neurodegeneration.