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Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats.

Sama DM, Mohmmad Abdul H, Furman JL, Artiushin IA, Szymkowski DE, Scheff SW, Norris CM - PLoS ONE (2012)

Bottom Line: To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling.Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca(2+) channel (VSCC) activity in hippocampal CA1 neurons.The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Gerontology, University of Kentucky, Lexington, Kentucky, United States of America.

ABSTRACT
The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca(2+) channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling.

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Effects of XPro1595 on glutamate receptor protein levels. A,Representative Western blots are shown for AMPA receptor (GluR1 and GluR2) and NMDA receptor subtypes (NR1, NR2A, and NR2B) in hippocampal membrane fractions from aged (22 month) rats treated for four weeks (intraventricular delivery) with vehicle or XPro1595 (0.08 mg/kg/day). The Na/K-ATPase loading control is shown below. B, XPro1595 treatment resulted in a selective increase in GluR1 levels (* p<0.05).
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pone-0038170-g004: Effects of XPro1595 on glutamate receptor protein levels. A,Representative Western blots are shown for AMPA receptor (GluR1 and GluR2) and NMDA receptor subtypes (NR1, NR2A, and NR2B) in hippocampal membrane fractions from aged (22 month) rats treated for four weeks (intraventricular delivery) with vehicle or XPro1595 (0.08 mg/kg/day). The Na/K-ATPase loading control is shown below. B, XPro1595 treatment resulted in a selective increase in GluR1 levels (* p<0.05).

Mentions: In addition to functional synaptic measures, we also used Western blot to assess glutamate receptor protein levels in membrane fractions from vehicle and XPro1595-treated rats. Protein markers included the AMPA receptor subunits GluR1 and GluR2, and the NMDA receptor subunits NR1, NR2A, and NR2B (Figure 4A). Nearly all of the glutamate receptor subunits investigated were insensitive to blockade of TNF/TNFR1 signaling (Figure 4A and 4B). The exception was GluR1, which showed strikingly higher membrane levels in XPro1595-treated aged rats (∼71% increase, p<0.05).


Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats.

Sama DM, Mohmmad Abdul H, Furman JL, Artiushin IA, Szymkowski DE, Scheff SW, Norris CM - PLoS ONE (2012)

Effects of XPro1595 on glutamate receptor protein levels. A,Representative Western blots are shown for AMPA receptor (GluR1 and GluR2) and NMDA receptor subtypes (NR1, NR2A, and NR2B) in hippocampal membrane fractions from aged (22 month) rats treated for four weeks (intraventricular delivery) with vehicle or XPro1595 (0.08 mg/kg/day). The Na/K-ATPase loading control is shown below. B, XPro1595 treatment resulted in a selective increase in GluR1 levels (* p<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3362564&req=5

pone-0038170-g004: Effects of XPro1595 on glutamate receptor protein levels. A,Representative Western blots are shown for AMPA receptor (GluR1 and GluR2) and NMDA receptor subtypes (NR1, NR2A, and NR2B) in hippocampal membrane fractions from aged (22 month) rats treated for four weeks (intraventricular delivery) with vehicle or XPro1595 (0.08 mg/kg/day). The Na/K-ATPase loading control is shown below. B, XPro1595 treatment resulted in a selective increase in GluR1 levels (* p<0.05).
Mentions: In addition to functional synaptic measures, we also used Western blot to assess glutamate receptor protein levels in membrane fractions from vehicle and XPro1595-treated rats. Protein markers included the AMPA receptor subunits GluR1 and GluR2, and the NMDA receptor subunits NR1, NR2A, and NR2B (Figure 4A). Nearly all of the glutamate receptor subunits investigated were insensitive to blockade of TNF/TNFR1 signaling (Figure 4A and 4B). The exception was GluR1, which showed strikingly higher membrane levels in XPro1595-treated aged rats (∼71% increase, p<0.05).

Bottom Line: To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling.Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca(2+) channel (VSCC) activity in hippocampal CA1 neurons.The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Gerontology, University of Kentucky, Lexington, Kentucky, United States of America.

ABSTRACT
The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca(2+) channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling.

Show MeSH
Related in: MedlinePlus