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

23 Citations (Scopus)

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
Pages (from-to)735-744
Number of pages10
JournalJournal of Neuropathology and Experimental Neurology
Volume72
Issue number8
DOIs
StatePublished - Aug 1 2013

Fingerprint

Thrombospondin 1
Amyloid
Astrocytes
Synaptophysin
Proteins
Alzheimer Disease
Oxidative Stress
Antioxidants
Thrombospondins
Neurons
Extracellular Matrix Proteins
Conditioned Culture Medium
Cognition
Peptides

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

Cite this

Amyloid-β inhibits thrombospondin 1 release from cultured astrocytes : Effects on synaptic protein expression. / Rama Rao, Kakulavarapu V.; Curtis, Kevin M.; Johnstone, Joshua T.; Norenberg, Michael D.

In: Journal of Neuropathology and Experimental Neurology, Vol. 72, No. 8, 01.08.2013, p. 735-744.

Research output: Contribution to journalArticle

@article{1a3f0e23bd6645949982d73821f4b217,
title = "Amyloid-β inhibits thrombospondin 1 release from cultured astrocytes: Effects on synaptic protein expression",
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.",
keywords = "Alzheimer disease, Amyloid-A, Astrocytes, Neurons, Oxidative stress, PSD95, Synaptophysin, Thrombospondin 1",
author = "{Rama Rao}, {Kakulavarapu V.} and Curtis, {Kevin M.} and Johnstone, {Joshua T.} and Norenberg, {Michael D}",
year = "2013",
month = "8",
day = "1",
doi = "10.1097/NEN.0b013e31829bd082",
language = "English",
volume = "72",
pages = "735--744",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Amyloid-β inhibits thrombospondin 1 release from cultured astrocytes

T2 - Effects on synaptic protein expression

AU - Rama Rao, Kakulavarapu V.

AU - Curtis, Kevin M.

AU - Johnstone, Joshua T.

AU - Norenberg, Michael D

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

AB - 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.

KW - Alzheimer disease

KW - Amyloid-A

KW - Astrocytes

KW - Neurons

KW - Oxidative stress

KW - PSD95

KW - Synaptophysin

KW - Thrombospondin 1

UR - http://www.scopus.com/inward/record.url?scp=84880921519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880921519&partnerID=8YFLogxK

U2 - 10.1097/NEN.0b013e31829bd082

DO - 10.1097/NEN.0b013e31829bd082

M3 - Article

C2 - 23860027

AN - SCOPUS:84880921519

VL - 72

SP - 735

EP - 744

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 8

ER -