Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease

Abstract

Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

Transcriptional characterization of the glial response due to chronic neural implantation of flexible microprobes

“…Since the presence of activated microglia can be detrimental to the neural environment, therefore the regulation of the microglia phenotype back to the default homeostatic state is essential for recovery (58,59). This change in phenotype is observed 2 weeks post implantation, where our data demonstrates an upregulation of Interleukin 13 ( Il13 , p=0.006), which has been shown to ameliorate neuroinflammation and promotes functional recovery (60).…”

Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review

“…Rather, activated and dystrophic microglia were present in cognitive dysfunction syndrome (CDS), a condition accompanied by tau synaptic impairment, in canines [ 81 ]. Additionally, microglial infiltration was identified around Aβ plaques and an increase in microglia was noted near NFT in pinnipeds (i.e., seals, sea lions, and walrus) [ 204 ]. Reactive microglial cells also have been localized in proximity to Aβ deposits in bovine brains [ 210 ].…”

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-β Associated Neurodegenerative Pathways and Glial Signatures in a Mouse Model of Alzheimer’s Disease: A Targeted Transcriptome Analysis

“…Eventually, all of these microglial profiles pointed to a common chronic primed microglia transcriptional signature established by gene co-expression meta-analysis ( 77 ), from which the results were built into the NanoString nCounter ® mouse neuropathology panel. Due to recent developments in scRNA-seq and targeted NanoString nCounter techniques, researchers have confirmed these earlier findings by further deciphering the various transcriptional subtypes and distinct stages of microglia that were interacting with Aβ plaques ( 56 – 59 , 99 , 100 ) ( Figure 5A ), thus converging age, sex, and AD risk genes as the major risk factors for AD ( 101 , 102 ). Importantly, critical microglial activation genes identified in amyloidosis mice were also recently validated in human AD brains ( 103 ).…”