Alzheimers disease (AD), the most common form of dementia, affects more than 50 million people worldwide, with no current treatment to halt the disease. The exact molecular mechanisms modulating disease progression remains elusive, even though numerous studies using mouse AD models have been done. In addition, as mouse models do not fully recapitulate human pathology, it is unclear to what extent results acquired from mouse models can be applied to treat humans. In this study, we conducted comprehensive bioinformatics analyses on transcriptomic profiles from mice bearing Abeta or tau pathology and human AD to identify differentially expressed genes (DEGs) and biological pathways shared among them. We identified the disease-associated microglia (DAM) signature and inflammatory pathways in both amyloid and tau mouse models compared to controls. Although GFAP was the only DEG shared by human AD and mouse AD models, pathways such as inflammatory response were identified in both human and mouse. Common pathways found in this study may modulate disease progression and provide new therapeutic targets.
Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.
Brain calcification, the ectopic mineral deposits of calcium phosphate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the Pdgfb ret/ret mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in Pdgfb ret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications.
Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.
Ubiquitous dissolved organic matter (DOM), a heterogeneous mixture with various organic components and continuous molecular weight (MW) distribution, can significantly influence the fate, bioavailability and toxicity of microplastics (MPs) in aquatic environments. However, to date, understanding of the MW-dependent adsorption heterogeneities of DOM on MPs in aquatic environments has remained unknown.In this study, the soil humic acid (HA), a representative DOM, was fractionated into >100 kDa HA, 30-100 kDa HA, 10-30 kDa HA, 3-10 kDa HA and <3 kDa HA, whose adsorption behaviors on polystyrene MPs (PSMPs) under different electrolytes at pH6.0 investigated by using total organic carbon, ultraviolet-visible absorption spectroscopy, fourier transform infrared spectroscopy, synchronous fluorescence (SF) spectroscopy coupled with two-dimensional correlation spectroscopy (SF-2D-COS)，as well as site energy distribution analysis. High molecular weight MW-fractionated HAs dominated the soil HA. The adsorption of the MW-fractionated HAs onto PSMPS can be reasonably explained by Langmuir and Freundlich isotherm models. Enhanced aromaticity in residual solutions after adsorption was observed. The heterogeneous/complicated distributions of active adsorption sites in the humic-like materials of the MW-fractionated HAs, and the subsequent subtle changes of these sites to PSMPs were characterized by SF-2D-COS. High molecular weight MW-fractionated HAs provided more active adsorption sites than those in the low molecular weight counterparts, which also possessed stronger adsorption affinities and higher complexation capacities to PSMPs. The adsorption heterogeneities of PSMPs at the experimental conditions were close. This study will help us better understand the biogeochemical behaviors of DOM and MPs in aquatic environments.
One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.
Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.
PSMPs-DOM formed under prolonged irradiation showed higher chlorine reactivity but lower THMs formation potential. The conversion of humic-like substances influenced the THMs formation potential, with C1 being a more dominant factor.
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