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P1‐184: INSULIN RESISTANT NEURONS ARISEN FROM PERIPHERAL HYPERINSULINEMIA ARE SENESCENT AND CORRELATE WITH MEMORY IMPAIRMENT AND COGNITIVE DECLINE: IMPLICATIONS FOR ALZHEIMER'S DISEASE
Author(s) -
Chow Hei-Man,
Shi Meng,
Zhang Jie,
Chen Guimiao,
Cheng Aifang,
Song Xuan,
Wai-Lam So Raphaella,
Herrup Karl
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.739
Subject(s) - hyperinsulinemia , insulin resistance , insulin , biology , hippocampal formation , neurodegeneration , endocrinology , medicine , cognitive decline , hippocampus , insulin receptor , neuroscience , disease , dementia
gamma(100nM), ATP(10uM), thapsigargin(10uM) and ionomycin(1uM). Dependence of stimulus-evoked responses on Kir2.1 potassium channels were examined using a selective blocker ML133(100uM). FlowJo was used for kinetic and quantitative analyses of data. Results: Acutely-isolated CNS-MPs demonstrated calciumflux in response to immune stimuli and thapsigargin, similar to BV2 microglia, establishing the validity of our flow assay.CD45 macrophages demonstrated higher basal calcium levels compared to CD45microglia.Microglia showed higher calcium flux in response to all three immune stimuli compared to macrophages. Interferongamma response was seen only in microglia (p1⁄40.02) Blockade of Kir2.1 channels significantly increased basal calcium levels in all CD45 macrophages, more evidently from 5xFAD mice (p1⁄40.017). Additionally, there is higher thapsigargin-induced calcium flux (p1⁄40.019) in CD45 microglia from 5xFADmice as compared to wild-type microglia. Conclusions: We established the validity of rapid flow-cytometric measurement of calcium flux in acutely-isolated mouse CNS-MPs. Microglia(CD45) and CD45 CNSMPs exhibit differences in calcium flux in response to LPS, IFNg and ATP, suggesting distinct mechanisms of immune-triggered calciumflux.Kir2.1 channels appear to playmajor roles in regulating calcium flux in CNS-MPs, particularly CD45 macrophages. Ongoing studies will define differences in calcium flux mechanisms between homeostatic and disease-associated microglia.