Jedrychowski, Mark P.

AbstractBackgroundMicroglia, the resident brain immune cells, play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA‐155 (miR‐155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear.MethodsWe used RNAseq and immunohistochemistry (n = 6‐8 per sex per group) to investigate the gene expression profile and AD pathology. We further utilized single‐cell RNAseq (n = 5 per group) to identify microglial clusters. Whole‐tissue proteomics (n = 4) was applied to detect the protein changes in brain milieu. Moreover, we used spontaneous alternation and forced alternation tests to evaluate the cognition (n = 33‐36).ResultWe report that microglial deletion of miR‐155 induces a pre‐MGnD activation state via interferon‐g (IFNg) signaling and blocking IFNg signaling attenuates MGnD induction and microglial phagocytosis. Single‐cell RNAseq analysis of microglia from AD mouse model identifies Stat1 and Clec2d as pre‐MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque‐associated synaptic degradation, and improves cognition.ConclusionOur study demonstrates a novel miR‐155‐mediated regulatory mechanism of MGnD and the beneficial role of IFNg‐responsive pre‐MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR‐155 and IFNg as potential therapeutic targets for AD.

Abstract In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human‐induced pluripotent stem cell‐derived neural cell types (excitatory neurons, astrocytes, microglia‐like cells, and oligodendrocyte‐like cells). Novel cell type‐specific EV protein markers were then identified for the excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), microglia‐like cells (ITGAM, LCP1), and oligodendrocyte‐like cells (LAMP2, FTH1), as well as 16 pan‐EV marker candidates, including integrins and annexins. To further demonstrate how cell‐type‐specific EVs may be involved in Alzheimer's disease (AD), we performed protein co‐expression network analysis and conducted cell type assessments for the proteomes of brain‐derived EVs from the control, mild cognitive impairment, and AD cases. A protein module enriched in astrocyte‐specific EV markers was most significantly associated with the AD pathology and cognitive impairment, suggesting an important role in AD progression. The hub protein from this module, integrin‐β1 (ITGB1), was found to be significantly elevated in astrocyte‐specific EVs enriched from the total brain‐derived AD EVs and associated with the brain β‐amyloid and tau load in independent cohorts. Thus, our study provides a featured framework and rich resource for the future analyses of EV functions in neurodegenerative diseases in a cell type‐specific manner.

Significance The work reported in this paper describes a previously unknown signaling pathway in skeletal muscle acting through G protein-coupled receptor 56-Galpha12/13. This discovery elucidates a previously unknown mechanism of muscle anabolism and gives another target of investigation for therapies against the loss of muscle mass seen with aging and various wasting diseases.