RESUMEN
Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aß), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent upon age and disease progression and is more prominent in the hippocampus in mice and humans. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD-laden microglia exhibited a deficit in Aß phagocytosis. Unbiased lipidomic analysis identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation. We demonstrate that DGAT2, a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting DGAT2 improved microglial uptake of Aß. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.
RESUMEN
Background The current trend in management of first-time primary spontaneous pneumothorax (PSP) in children is to obtain a high-resolution chest computerized tomography (HRCT) scan to look for bleb/bullae disease or other forms of structural lung disease. We aimed to evaluate the significance of HRCT findings in relation to initial management strategies, and we hypothesized that these findings do not guide management. Methods We evaluated patients with first-time PSP in a single-institution, retrospective, longitudinal study. Data were obtained through direct chart review. The primary endpoint was the percentage of patients who underwent surgical intervention after HRCT. Results We identified 10 children from 10 to 17 years old from January 2013 to November 2019 who met criteria for the study. Seven out of 10 patients (70%) had HRCT after the first-time PSP during the same hospital stay. Blebs/bullae were discovered in five out of seven (71%) of those patients. Two of those five patients had subsequent surgical intervention (40%) before a recurrence. Of the three patients with blebs/bullae identified on HRCT treated without initial surgery, two had a recurrence of PSP and subsequently underwent VATS with blebectomy and pleurodesis. Among the patients without initial HRCT, there were no recurrent cases of PSP noted. Conclusions Our study suggests there is value in obtaining HRCT after the first time PSP, as these results can be used to guide management strategies. Further studies in pediatric PSP are needed to validate the sensitivity of HRCT in bleb detection, the predictive value of bleb disease and recurrence, and the benefits and risks of early surgical intervention.
RESUMEN
BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor and has a dismal prognosis. Previously, we identified that junctional adhesion molecule A (JAM-A), a cell adhesion molecule, is highly elevated in human GBM cancer stem cells and predicts poor patient prognosis. While JAM-A is also highly expressed in other cells in the tumor microenvironment, specifically microglia and macrophages, how JAM-A expression in these cells affects tumor growth has yet to be determined. The goal of this study was to understand the role of microenvironmental JAM-A in mediating GBM growth. METHODS: Male and female wild-type (WT) and JAM-A-deficient mice were transplanted intracranially with the syngeneic glioma cell lines GL261 and SB28 and were assessed for differences in survival and microglial activation in tumors and in vitro. RNA-sequencing was performed to identify differentially regulated genes among all genotypes, and differences were validated in vitro and in vivo. RESULTS: We found that JAM-A-deficient female mice succumbed to GBM more quickly compared with WT females and JAM-A-deficient and male WT mice. Analysis of microglia in the tumors revealed that female JAM-A-deficient microglia were more activated, and RNA-sequencing identified elevated expression of Fizz1 and Ifi202b specifically in JAM-A-deficient female microglia. CONCLUSIONS: Our findings suggest that JAM-A functions to suppress pathogenic microglial activation in the female tumor microenvironment, highlighting an emerging role for sex differences in the GBM microenvironment and suggesting that sex differences extend beyond previously reported tumor cell-intrinsic differences.
