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P2‐181: IL‐1β INFLUENCES AUTOPHAGY BY MEDIATING UPREGULATION OF PARKIN AND PARKIN NEDDYLATION IN CELL CULTURE AND ANIMAL MODELS, AND MIMICS THE PATTERN SEEN IN AD BRAIN
Author(s) -
Griffin Sue T.,
Parcon Paul Andrew,
Balasubramaniam Meenakshisundaram,
Bose Chhanda,
Ayyadevara Srinivas,
Jones Richard A.,
Farlow Martin R.,
Mrak Robert E.
Publication year - 2018
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.2018.06.868
Subject(s) - parkin , nedd8 , autophagy , neuroinflammation , microbiology and biotechnology , ubiquitin , neddylation , ubiquitin ligase , biology , hippocampal formation , hippocampus , neuroscience , chemistry , immunology , biochemistry , apoptosis , medicine , inflammation , disease , parkinson's disease , gene
results were compared to those of 20 healthy sex and age matched healthy controls(HC). Mechanisms regulating inflammasome signaling involves the priming signal to upregulate the expression of NLRP3 and signal 2 to activate the functional NLRP3; thus monocytes were either primed with LPS(1mg/ml for 2h) and stimulated with Aß42 AlexaFluor488 (FAM)-labeled (10mg/ml) for 24h or stimulated with Aß42 FAM alone for 24h in the presence/absence of Stavudine (50mM) for 22h. Aß-phagocytosis was analyzed by Imagines–FlowCitometry; caspase1 and cytokines were quantified by ELISA. Results: Results showed that: 1) Caspase1, IL1ß and IL18 production by LPS and Aß42 stimulated monocytes of AD patients was significantly increased compared to HC (for all p<0.05); 2) Aß-phagocytosis was significantly reduced in LPS-primed and Aß42 stimulated cells of AD and HC individuals compared to those stimulated with Aß42 alone (for both p<0.05); 3) Stavudine resulted in a drastic reduction of Caspase1, IL1ß and IL18 production (p<0.05) but did not modify the Aß-phagocytosis capacity of monocytes. Conclusions:NLRP3 inflammasome-driven inflammation reduces monocytes mediated Aß phagocytosis in AD and HC. Stavudine dampens NLRP3 activation and downstream inflammation but does not significantly modify Aß-phagocytosis. These results suggest that, even if Stavudine could be useful in modulating neuroinflammation in AD, AD-associated impairments in Aßphagocytosis are not a consequence of a direct consequence of inflammation.