Transcriptomically unique endolysosomal and homeostatic microglia populations in Alzheimer’s disease and aged human brain

Abstract

Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer's Disease (AD). Microglia demonstrate heterogeneous states in health and disease, with proposed beneficial, harmful, and disease specific subtypes. Defining the spectrum of microglia phenotypes is an important step in rational design of neuroinflammation modulating therapies. To facilitate improved phenotype resolution and group comparisons based on disease state we performed single-nucleus RNA-seq on more than 120,000 microglia nuclei from AD and control dorsolateral prefrontal cortex. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles. We detected several previously unrecognized microglia populations in human AD brain, including three internalization and trafficking subtypes that were heterogeneous in their metabolic and inflammatory signatures. One of these endolysosomal subtypes is larger in AD individuals and was uniquely enriched for genes involved in nucleic acid detection and activation of interferon signaling. This inflammatory endolysosomal cluster also differentially regulated expression of genes associated with AD risk by genome wide association studies. We also identified a cluster of microglia with upregulated cell cycle and DNA repair genes that is proportionately larger in control individuals. Within cluster comparisons demonstrate that in AD brain, homeostatic microglia subpopulations upregulate inflammatory gene expression. These results highlight the heterogenous nature of the microglia response to AD pathology and will inform efforts to target specific subtypes of microglia in the development of novel AD therapies.

A single-cell multi-omic atlas spanning the adult rhesus macaque brain

“…Transcription factors (TFs) are key trans-regulatory proteins that control cell differentiation and function during neurodevelopment [48, 49, 50, 51] and have been implicated in myriad neurode-generative diseases [52, 53, 54]. The extremely high cell-type specificity of some nuclear TFs have also made them useful targets for identifying and enriching rarer cell types prior to single-cell sequencing [55, 56, 57].…”

“…Transcription factors (TFs) are key trans-regulatory proteins that control cell differentiation and function during neurodevelopment [48,49,50,51] and have been implicated in myriad neurodegenerative diseases [52,53,54]. The extremely high cell-type specificity of some nuclear TFs have also made them useful targets for identifying and enriching rarer cell types prior to single-cell sequencing [55,56,57]. To identify candidate trans-acting regulatory networks in each cell class, we carried out TF binding motif enrichment analysis on each set of cell-class-specific peaks, defined as the subset of a cell class's cCREs that did not overlap with any peaks called in other cell classes (Methods, Fig.…”

1-L Transcription in Alzheimer’s Disease

“…Cellular polyamine homeostasis must be tightly controlled; excessive concentrations of polyamines induce cellular toxicity [ 59 ]. ATP13A3 was significantly upregulated in transcriptomic profiling of myeloid cells in AD brains compared to controls [ 60 ].…”

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies

“…Genome wide association studies and single-cell genomic studies in AD have identified many risk genes that expressed in microglia and the critical role of neuroimmune pathways chronic inflammatory states for AD (38,55). Moreover transcriptomic studies have found diverse and substantial astrocyte and microglial responses to show the most changes in response to AD pathology in murine and human studies (34,53,63). Microglial activation visualized by positron emission tomography (PET) has been shown to correlate with Aβ and tau loads (12,14,71), propagate jointly with tau across Braak stages (49), and cognitive decline in AD (41).…”