Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats.
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.
Graduate Center for Gerontology, University of Kentucky, Lexington, Kentucky, United States of America.
Diana M
DM
Sama
Hafiz
H
Mohmmad Abdul
Jennifer L
JL
Furman
Irina A
IA
Artiushin
David E
DE
Szymkowski
Stephen W
SW
Scheff
Christopher M
CM
Norris
D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003866:Depressive Disorder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D018091:Receptors, AMPA / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012995:Solubility; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
D002118:Calcium; D020746:Calcium Channels, L-Type; D018091:Receptors, AMPA; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha