Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease

Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models

“…Next, we sought to confirm the presence of these markers in the astrocytes in human post-mortem brain samples. We selected a cohort of AD patient and age-matched non-symptomatic (NS) controls ( Sadick et al, 2022 ) and stained formalin-fixed paraffin embedded frontal cortex samples for our putative reactive astrocyte markers. Broadly, we report no or minimal immunofluorescence for any marker in the NS brain.…”

“…A recent study using hiPSC modeling has classified TIC-induced reactive astrocytes into at least two distinct subpopulations using single-cell sequencing (scRNA-seq) analyses and CRISPRi screening ( Leng et al, 2021 ); however, deeper characterization of these subpopulations is hindered by the lack of specific markers that enable their purification. Furthermore, although several transcriptomic datasets have been generated using rodents ( Clarke et al, 2018 ; Pan et al, 2020 ; Hasel et al, 2021 ), human models ( Teh et al, 2017 ; Barbar et al, 2020a ), and human post-mortem brain samples ( Mathys et al, 2019 ; Zhou et al, 2020 ; Sadick et al, 2022 ), studies on the proteome of human reactive astrocytes are still limited.…”

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

“…In addition to these direct effects of inflammatory mediators on cellular plasticity in the brain, microglia also induce neurotoxic astrocyte reactivity through cytokine signaling (Liddelow et al, 2017). Astrocytes can assume a range of reactive states (Hasel et al, 2021;Sadick et al, 2022) that can induce further pathophysiology, with certain states of reactive astrocytes inducing oligodendrocyte and neuronal cell death (Liddelow et al, 2017;Guttenplan et al, 2021). Additionally, this substate of reactive astrocytes are poor supporters of synaptic connections-further adding to network dysfunction (Liddelow et al, 2017).…”

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

“…Few changes in astrocyte numbers are detected in 5x-FIRE mice Astrocytes can also respond to amyloid plaques and microglialastrocytic crosstalk plays an important role in AD pathogenesis (Liddelow et al, 2017;Sadick et al, 2022). We therefore examined the density of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes within the cortex, hippocampus, and thalamus and quantified astrocytic proximity to amyloid plaques (Figure S8).…”