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: Contribution to journalArticle

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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
Presenilin-1
Neurons
Calpain
Calcium
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: Contribution to journalArticle

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