Microglial pathology

Abstract

This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer’s disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial pathology and its significance during aging and in the pathogenesis of Alzheimer dementia (AD). The identification of dystrophic (senescent) microglia has created an ostensible conflict with prior work claiming a role for activated microglia and neuroinflammation during normal aging and in AD, and this has raised a basic question: does the brain’s immune system become hyperactive (inflamed) or does it become weakened (senescent) in elderly and demented people, and what is the impact on neuronal function and cognition? Here we strive to reconcile these seemingly contradictory notions by arguing that both low-grade neuroinflammation and microglial senescence are the result of aging-associated free radical injury. Both processes are damaging for microglia as they synergistically exhaust this essential cell population to the point where the brain’s immune system is effete and unable to support neuronal function.

Iron, Aging, and Neurodegeneration

“…Microglia maintain homeostasis in the healthy brain and fight infection when it is present through a complicated system of signaling molecules. The importance of microglia to neurons is supported by a higher incidence of dystrophic microglia and microglial apoptosis in AD [150]. The inflammation of the nervous system in neurodegenerative disease was thought to be due to activated microglia.…”

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

“…In frontal and temporal grey matter, which displayed a similar burden of other pathology compared with white matter, Iba1 positive microglia were typically amoeboid, rather than dystrophic, in appearance. This dissociation between degree of microglial dystrophy and other pathology suggests that there may be region-specific microglial dystrophy in GRN mutation carriers, perhaps due to premature microglial dysfunction or senescence (Streit, Xue, Tischer, & Bechmann, 2014) secondary to GRN haploinsufficiency. As Iba1 expression may reflect microglial motility (Minett et al, 2016), microglia may be less motile in frontal white matter of GRN mutation carriers.…”

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Mononuclear phagocyte morphology was defined according to previous work [58] To quantify degeneration of mononuclear phagocytes in ALS patients, an observer blinded to the genotype scored from 0 to 4 the occurrence of degeneration in 2-5 sections per patient, with a score of 0 for sections showing nondegenerating phagocytes. Features of microglial degeneration were according to Streit and collaborators [58].…”

“…However, our in vitro experiments provide an initial proof of concept that microglial survival could be influenced by serotonergic stimulation of the 5-HT 2B R. Further work is required to determine the relative contributions of microglial cell death and altered microglial phenotypes in the observed degenerative phenotype in vivo as well as the importance of monocyte degeneration. Interestingly, degeneration of mononuclear phagocytes is commonly associated with human neurodegenerative diseases, and commonly referred to as microglial degeneration [58], whereas rodent models appear less affected by this phenotype. However, previous studies observed degeneration of mononuclear phagocytes in a transgenic mutant SOD1 rat [24], similar to our current results in mutant SOD1 mice carrying a wild type Htr2b gene.…”

“…Importantly, microglia lose the expression of their homeostatic signature during disease progression [12,7], and develop unique expression patterns during experimental ALS distinct from inflammation-induced alteration [12,7]. This loss of typical microglial expression patterns could be directly correlated with degeneration of CNS macrophages, documented in different neurodegenerative diseases [58,57,69] including a transgenic model of ALS [24,58]. Whether macrophage degeneration is microglia specific or also occurs in infiltrating monocytes, and whether this degeneration might be involved in neurodegeneration is not known.…”