Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases

Li Liu, Rebecca Martin, Christina Chan

Research output: Contribution to journalArticle

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Abstract

Astrocytes play a critical role in neurodegenerative diseases, including Alzheimer's disease (AD). Previously, we showed that saturated free fatty acid, palmitic acid (PA), upregulates β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) level and amyloidogenesis in primary rat neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from PA-treated astrocytes upregulates BACE1 level in neurons are unknown. This study demonstrates that serine palmitoyltransferase (SPT) in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (SMase) in the neurons, to propagate the deleterious effects of PA (i.e., BACE1 upregulation). In support of the relevance of SPT in AD, our laboratory recently measured and found SPT levels to be significantly upregulated in AD brains as compared with controls. Cytokines, namely tumor necrosis factor-α and interleukin-1β, released into the conditioned media of PA-treated astrocytes activate neural and acidic SMase in the neurons. Neutralizing the cytokines in the PA-treated astrocyte conditioned media reduced BACE1 upregulation. However, inhibiting SPT in the astrocytes decreased the levels of both tumor necrosis factor-α and interleukin-1β in the conditioned media, which in turn reduced the SMase activities and BACE1 level in primary neurons. Thus, our results suggest that the activation of the astrocytes by PA is mediated by SPT, and the activated astrocytes increases BACE1 level in the neurons; the latter is mediate by the SMases.

LanguageEnglish (US)
Pages540-550
Number of pages11
JournalNeurobiology of Aging
Volume34
Issue number2
DOIs
StatePublished - Feb 2013

Profile

Serine C-Palmitoyltransferase
Sphingomyelin Phosphodiesterase
Palmitates
Astrocytes
Palmitic Acid
Neurons
Conditioned Culture Medium
Up-Regulation
Alzheimer Disease
Cytokines
Interleukin-1beta
Tumor Necrosis Factor-alpha
Amyloid beta-Protein Precursor
Ceramides
Nonesterified Fatty Acids
Neurodegenerative Diseases
Fatty Acids

Keywords

  • Alzheimer's disease
  • Ceramide; TNF-α
  • Fatty acid
  • IL-1β
  • Serine palmitoyltransferase
  • Sphingomyelinase

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases. / Liu, Li; Martin, Rebecca; Chan, Christina.

In: Neurobiology of Aging, Vol. 34, No. 2, 02.2013, p. 540-550.

Research output: Contribution to journalArticle

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