Inhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease

Abstract

Microglial dystrophy has recently been described as a morphological phenotype of microglia that differs from resting and activated states by spheroid formation and cytorrhexis. In thick sections immunolabeled for HLA-DR or Iba-1 dystrophic microglial processes lose their typical, homogeneous staining pattern and appear to be fragmented or clustered. In this study, we performed double immunofluorescence and electron microscopy to determine if this labeling pattern indeed reflects complete separation of microglial processes from the soma. Using Iba-1/CD68 and Iba-1/MHC class II, as microglial markers, we observed that isolated Iba-1 fragments were still connected to each other by segments of the microglial process immune positive for CD68 or MHC class II. Ultrathin serial sections of two Iba-1 fragments which appeared to be disconnected from each other at the light microscopical level revealed a still existing "bridge" with a diameter of around 0.182 µm. Therefore, microglial dystrophy may reflect alterations of the cytoskeleton ultimately leading to slow cytorrhexis. GLIA 2016;64:1562-1572.

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

“…As Iba1 expression may reflect microglial motility (Minett et al, 2016), microglia may be less motile in frontal white matter of GRN mutation carriers. A reduction in Iba1 positive microglia was observed in patients with AD using similar microglial markers (Minett et al, 2016), and Iba1 positive dystrophic microglia are present in AD cases (Streit et al, 2009; Tischer et al, 2016), preceding the spread of tau pathology (Streit et al, 2009). Impaired microglial motility or function within regions such as frontal and temporal white matter could reduce neuronal support, leading to white matter vulnerability in GRN mutation carriers that develop WMH.…”

“…Three antibodies were used to detect microglia with differing phenotypes, in both ramified and activated states: cluster of differentiation CD68 (CD68), which detects a lysosomal and endolyosomal glycoprotein upregulated in activated, phagocytic microglia; CR3/43, which detects human leucocyte antigen-DR (HLA-DR), a molecule expressed by microglia with antigen presenting cell function and upregulated in inflammation; and ionized calcium-binding adapter molecule 1 (Iba1), which is expressed by resting microglia but upregulated on activated microglia, may reflect microglial motility, and is useful for assessing microglial morphology (Minett et al, 2016; Streit, Braak, Xue, & Bechmann, 2009; Tischer et al, 2016). …”

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

“…The pathology was characterized by shortened and less branched processes that usually were deformed, displaying cytoplasmic abnormalities (including spheroids) and even fragmentation (cytorrhexis), although this could be due to pathological redistribution of the microglial markers (see also Refs. [54, 57]).…”

“…This degenerative process was more prominent in the hilar region of the dentate gyrus and the CA3 region of the hippocampus proper. The microglial pathology is characterized by the following: (1) the presence of degenerative microglial cells, which exhibit shortened and less branched processes, cytoplasmic fragmentation (cytorrhexis) and spheroids formation (see also [54, 57]); (2) a reduction (at least in 4 of 9 Braak V–VI cases tested) in the microglial numerical density; and (3) a dramatic decrease in the area of surveillance of individual microglial cells, described here as the microglial domain. These pathological modifications produce a prominent decrease in the parenchymal area covered by microglia in these particular hippocampal subfields (DG and CA3), leaving most of the parenchymal space with no immune coverage, including Abeta plaques and vascular Abeta depositions.…”

Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases

“…Altered microglia morphology and reduced arborization have been reported in the human brain during aging and in AD patients (Davies et al, 2016). It remains unclear whether the observed morphological changes are signs of microglia degeneration and a recent study suggests that the reported microglia dystrophy might reflect age-related cytoskeleton alterations (Tischer et al, 2016). Interestingly, direct Tau uptake by microglia has been reported (Bolós et al, 2016) and is enhanced by anti-tau antibodies in an Fc-receptor-dependent manner (Luo et al, 2015).…”