Dystrophic microglia are a disease associated microglia morphology in the human brain

Abstract

Microglia activation—typically described in terms of hypertrophic appearance—is a well-established feature of aging. Recent studies have suggested that microglia dystrophy, not activation, may increase the propagation of progressive neurodegenerative diseases such as Alzheimer’s disease (AD). Yet, a clear understanding of cause and consequences of dystrophic microglia is lacking. Although frequently observed in diseased brains, the appearance of dystrophic microglia in the hippocampus of individuals free of cognitive impairment suggests that microglia may be undergoing senescence with age, leading to dystrophy. Therefore, we hypothesized that chronological age could be a significant contributor to the presence of dystrophic microglia. To investigate this relationship, we employed stereological counts of total microglia, hypertrophic, and dystrophic microglia across the decades of the human lifespan. The microglia counts were performed in the frontal cortex gray and white matter and the CA1 subregion of the hippocampus in individuals without known neurodegenerative disease. There was age-associated increase in the number of dystrophic microglia in the CA1 region and the frontal cortex gray matter related to age. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia, suggesting that aging alone was not sufficient to explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia phenotype. Compared to controls without neuropathology, the number of dystrophic microglia was significantly greater in aged-matched cases with either AD, dementia with Lewy bodies, or LATE-NC. These results provide evidence that healthy aging is only associated with a modest increase in dystrophic microglia and suggest that dystrophic microglia may be a disease-associated microglia phenotype. Finally, we found strong evidence for iron homeostasis changes, with increases in ferritin light chain, in dystrophic microglia compared to ramified or hypertrophic microglia. Based on our findings, microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Future work is required to understand the links between the increase in dystrophic microglia and neurodegenerative disorders.

Histopathological assessments reveal retinal vascular changes, inflammation and gliosis in patients with lethal COVID-19

“…Chronological aging is associated with a significant increase in the total numbers of both hypertrophic as well as dystrophic microglia. A recent study showed that dystrophy are the disease associated microglia morphology 21 . In the present study we see evidence for increased microglial cells in the COVID-19 eyes and several of these appear to show the characteristic of microglial dystrophy and hypertrophy.…”

“…As a result of aging, an increasing proportion of microglial cells display abnormal morphological features such as shortened, gnarled, beaded, or fragmented cytoplasmic processes, and loss of fine ramifications and formation of spheroidal swellings; these changes are designated collectively as microglial dystrophy 20 . These changes are determined to be different than what occurs during microglial activation which is defined as hypertrophic microglia [20][21][22][23] . In all the eyes examined, there was evidence for both hypertrophic and dystrophic microglia, though there was evidence of microglial dystrophy in 2.…”

Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimer’s Disease

“…We next sought to explore whether our DS microglial mouse chimera could recapitulate the dystrophic microglia pathology found in AD and DSAD human brain tissues (Braak and Del Tredici, 2015; Jimenez et al, 2008; Martini et al, 2020; Meyer-Luehmann and Prinz, 2015; Sanchez-Mejias et al, 2016; Shahidehpour et al, 2020; Streit et al, 2009; Xue and Streit, 2011). Previous in vitro studies demonstrated that soluble p-tau in human AD brain tissue extracts induced microglial degeneration (Sanchez-Mejias et al, 2016).…”

“…Although the amyloid cascade/neuroinflammation theory of AD has been widely accepted, several caveats have arisen. The microglial responses observed in the hippocampus of APPbased mouse models differ from those observed in AD and DSAD patients (Braak and Del Tredici, 2015;Jimenez et al, 2008;Meyer-Luehmann and Prinz, 2015;Sanchez-Mejias et al, 2016;Shahidehpour et al, 2020;Streit et al, 2009;Xue and Streit, 2011). More importantly, non-steroidal anti-inflammatory drugs have demonstrated no clear ability to delay onset or reverse cognitive dysfunction in AD patients (Arvanitakis et al, 2008;Green et al, 2009;Group et al, 2007;Group et al, 2008).…”

Evaluation of Macular Retinal Vessels and Histological Changes in Two Cases of COVID-19

“…Microglial cells changed with an increase in ramified morphology, and most migrated to the retinal vessels in the GCL and nerve fiber layer. Recent studies have shown that dystrophy is a disease associated with microglial morphology [ 32 ] and brain alterations in COVID-19 [ 33 ].…”