title: Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes.
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.
authors: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
authors: Li
authors: L
authors: Liu
authors: Rebecca
authors: R
authors: Martin
authors: Garrett
authors: G
authors: Kohler
authors: Christina
authors: C
authors: Chan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D010766:Phosphorylation; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D053763:Presenilins; D050796:STAT3 Transcription Factor; D019308:Palmitic Acid; D051360:Cyclin-Dependent Kinase 5; D053829:Amyloid Precursor Protein Secretases; D002154:Calpain; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D002118:Calcium
keywords: Alzheimer's disease; BACE1; Calcium; Fatty acids; Presenilin-1; STAT3
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