Amyloid-β inhibits thrombospondin 1 release from cultured astrocytes: Effects on synaptic protein expression

Kakulavarapu V. Rama Rao, Kevin M. Curtis, Joshua T. Johnstone, Michael D. Norenberg

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Among the consequences of Alzheimer disease are disturbances in synaptic integrity that ultimately lead to impaired cognitive functions. Thrombospondins are extracellular matrix proteins that, in the CNS, are predominantly produced by astrocytes and have been implicated in synaptogenesis. This study examined the effects of amyloid-β (Aβ1-42; Aβ) peptide on intracellular and extracellular levels of thrombospondin 1 (TSP-1) in cultured astrocytes. Amyloid-β caused a significant (1- to 3-fold) increase in astrocytic intracellular levels of TSP-1 (increased retention) that was associated with a reduction of its release from astrocytes. Because Aβ is known to induce oxidative stress in astrocytes, we examined the effects of the antioxidants tempol and apocynin on astrocytic TSP-1 levels and release. Treatment of Aβ-exposed astrocyte cultures with antioxidants significantly diminished its cellular retention and stimulated its release. Furthermore, the addition of conditioned media derived from Aβ-treated cultured astrocytes that contained a reduced TSP-1 content resulted in a significant loss of synaptophysin and PSD95 in cultured neurons. These findings suggest that Aβ-mediated reduction in astrocytic TSP-1 release, possibly related to oxidative stress, contributes to the loss of synaptophysin in neurons. Strategies aimed at enhancing the astrocytic release of TSP-1 may have a therapeutic benefit in Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)735-744
Number of pages10
JournalJournal of neuropathology and experimental neurology
Volume72
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Alzheimer disease
  • Amyloid-A
  • Astrocytes
  • Neurons
  • Oxidative stress
  • PSD95
  • Synaptophysin
  • Thrombospondin 1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

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