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Presenilin 2 influences miR146 level and activity in microglia
Author(s) -
Jayadev Suman,
Case Amanda,
Alajajian Betty,
Eastman Alison J.,
Möller Thomas,
Garden Gwenn A.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12400
Subject(s) - microglia , neurodegeneration , biology , neuroinflammation , presenilin , proinflammatory cytokine , inflammation , immunology , alzheimer's disease , innate immune system , neuroscience , immune system , microbiology and biotechnology , medicine , disease
Microglia, the resident innate immune cells of the CNS , are the primary defenders against microbes and critical to CNS remodeling. Dysregulation of microglial behavior can lead to unchecked pro‐inflammatory activity and subsequent neurodegeneration. The molecular mechanisms leading to chronic inflammation and microglial dysfunction in neurodegenerative diseases are not well‐understood. It is known that patients with Presenilin 2 ( PS 2) mutations develop autosomal dominant Alzheimer disease. We have shown that a lack of normal PS 2 function is associated with exaggerated microglia pro‐inflammatory responses in vitro . To identify pathways by which PS 2 regulates microglia and determine how PS 2 dysfunction may lead to altered inflammatory pathways, we pursued an unbiased array approach to assess differential expression of micro RNA s between murine PS 2 knockout ( KO ) and wild‐type microglia. We identified miR146, a negative regulator of monocyte pro‐inflammatory response, as constitutively down‐regulated in PS 2 KO microglia. Consistent with a state of miR146 suppression, we found that PS 2 KO microglia express higher levels of the miR146 target protein interleukin‐1 receptor‐associated kinase‐1, and have increased NF κB transcriptional activity. We hypothesize that PS 2 impacts microglial responses through modulation of miR146a. PS 2 dysfunction, through aging or mutation, may contribute to neurodegeneration by influencing the pro‐inflammatory behavior of microglia.Presenilin 2 (PS2), a membrane associated protease, has been implicated in the pathogenesis of Alzheimer disease. We have previously shown that PS2 plays an important role in curbing the proinflammatory response in microglia. Here, we report the novel finding that PS2 participates in maintaining the basal and cytokine induced expression of the innate immunity regulating microRNA, miR146. These data suggest one mechanism by which PS2 works to reign in proinflammatory microglial behavior and that PS2 dysfunction or deficiency could thus result in unchecked proinflammatory activation contributing to neurodegeneration.