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 language | English |
|---|---|
| Pages (from-to) | 735-744 |
| Number of pages | 10 |
| Journal | Journal of Neuropathology and Experimental Neurology |
| Volume | 72 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2013 |
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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 journal › Article
}
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 -