Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Li Liu, Rebecca Martin, Garrett Kohler, Christina Chan

    Research output: Research - peer-reviewArticle

    • 13 Citations

    Abstract

    Deregulation of calcium has been implicated in neurodegenerative diseases, including Alzheimer's disease (AD). Previously, we showed that saturated free-fatty acid, palmitate, causes AD-like changes in primary cortical neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned medium from astrocytes cultured in palmitate induce AD-like changes in neurons are unknown. This study demonstrates that this condition medium from astrocytes elevates calcium level in the neurons, which subsequently increases calpain activity, a calcium-dependent protease, leading to enhance p25/Cdk5 activity and phosphorylation and activation of the STAT3 (signal transducer and activator of transcription) transcription factor. Inhibiting calpain or Cdk5 significantly reduces the upregulation in nuclear level of pSTAT3, which we found to transcriptionally regulate both BACE1 and presenilin-1, the latter is a catalytic subunit of γ-secretase. Decreasing pSTAT3 levels reduced the mRNA levels of both BACE1 and presenilin-1 to near control levels. These data demonstrate a signal pathway leading to the activation of STAT3, and the generation of the amyloid peptide. Thus, our results suggest that STAT3 is an important potential therapeutic target of AD pathogenesis.

    LanguageEnglish (US)
    Pages482-490
    Number of pages9
    JournalExperimental Neurology
    Volume248
    DOIs
    StatePublished - Oct 2013

    Profile

    Presenilins
    Palmitates
    Astrocytes
    Alzheimer Disease
    Neurons
    Calcium
    Presenilin-1
    Calpain
    Amyloid Precursor Protein Secretases
    Conditioned Culture Medium
    Transducers
    Nonesterified Fatty Acids
    Amyloid
    Neurodegenerative Diseases
    Signal Transduction
    Catalytic Domain
    Peptide Hydrolases
    Transcription Factors
    Up-Regulation
    Fatty Acids

    Keywords

    • Alzheimer's disease
    • BACE1
    • Calcium
    • Fatty acids
    • Presenilin-1
    • STAT3

    ASJC Scopus subject areas

    • Neurology
    • Developmental Neuroscience

    Cite this

    Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes. / Liu, Li; Martin, Rebecca; Kohler, Garrett; Chan, Christina.

    In: Experimental Neurology, Vol. 248, 10.2013, p. 482-490.

    Research output: Research - peer-reviewArticle

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