Inhibition of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations and Ca2+ Dysregulation in Aged Rats

Sama, Diana M.; Abdul, Hafiz Mohmmad; Furman, Jennifer L.; Artiushin, Irina A.; Szymkowski, David E.; Norris, Christopher M.

doi:10.1371/journal.pone.0038170

Cited by 51 publications

(54 citation statements)

References 94 publications

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“…Later work showed that the magnitude of LTD in aged rats correlates with the extent of memory dysfunction, as measured by the Morris Water Maze (Foster and Kumar, 2007). While these observations have been largely confirmed by subsequent studies from several different research groups, (Foy et al, 2008; Hsu et al, 2002; Norris et al, 1998a; Sama et al, 2012; Vouimba et al, 2000) other studies did not detect LTD in aged animals or did not find an age difference (Billard and Rouaud, 2007; Kollen et al, 2010; Lee et al, 2005). Like LTP, these discrepancies may be attributable to differences in experimental protocol, especially in regard to synaptic stimulation frequencies and extracellular Ca 2+ content (see Norris et al, 1996; Foster and Norris, 1997; Kumar et al, 2007; Mathis et al, 2011).…”

Section: Synaptic Plasticitymentioning

confidence: 51%

“…Alterations in synaptic plasticity, including reduced LTP have been observed in healthy CNS tissue following acute application of IL-1β or TNFα (Bellinger et al, 1993; Cunningham et al, 1996; Katsuki et al, 1990; Tancredi et al, 1992). Conversely, treatments that reduce IL-1β or TNFα levels, or inhibit cytokine receptor activation, generally improve indices of synaptic function and/or neuronal viability in experimental models of neuroinflammation and disease (Bachstetter et al, 2012; Kelly et al, 2001; McCoy et al, 2006; Sama et al, 2012; Sama et al, 2008). These effects are likely caused by signaling within the neurons and surrounding glial cells.…”

Section: Neuroinflammationmentioning

confidence: 99%

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Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction

Sama¹,

Norris²

2013

Ageing Research Reviews

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100

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Some of the best biomarkers of age-related cognitive decline are closely linked to synaptic function and plasticity. This review highlights several age-related synaptic alterations as they relate to Ca2+ dyshomeostasis, through elevation of intracellular Ca2+, and neuroinflammation, through production of pro-inflammatory cytokines including interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Though distinct in many ways, Ca2+ and neuroinflammatory signaling mechanisms exhibit extensive cross-talk and bidirectional interactions. For instance, cytokine production in glial cells is strongly dependent on the Ca2+ dependent protein phosphatase calcineurin, which shows elevated activity in animal models of aging and disease. In turn, pro-inflammatory cytokines, such as TNF, can augment the expression/activity of L-type voltage sensitive Ca2+ channels in neurons, leading to Ca2+ dysregulation, hyperactive calcineurin activity, and synaptic depression. Thus, in addition to discussing unique contributions of Ca2+ dyshomeostasis and neuroinflammation, this review emphasizes how these processes interact to hasten age-related synaptic changes.

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Section: Synaptic Plasticitymentioning

confidence: 51%

Section: Neuroinflammationmentioning

confidence: 99%

Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction

Sama¹,

Norris²

2013

Ageing Research Reviews

Self Cite

100

View full text Add to dashboard Cite

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“…Future studies will be aimed at determining the extent to which the restoration of LTP resulting from sTNF signaling inhibition was due to decreased amyloid deposition in the hippocampus or via direct effect on synaptic physiology. However, given that TNF can inhibit LTP (Cunningham et al, 1996) and that sTNF promotes long-term depression (LTD) in aged rats (Sama et al, 2012), our findings with XPro1595 in 5xFAD mice strongly suggest that sTNF is likely to be directly mediating the LTP deficits in Tg mice. sTNF has been shown to play an important role in potentiating glutamate excitotoxicity, through direction activation of NMDA receptors and increasing AMPA receptor localization at the synapse, while transmembrane TNF/TNFR2 signaling has been implicated in protection against excitotoxicity (McCoy and Tansey, 2008).…”

Section: Discussionmentioning

confidence: 75%

Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice

MacPherson

Sompol

Kannarkat

et al. 2017

Neurobiology of Disease

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113

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Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer’s disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII+, CD45high, and Ly6Chigh) myeloid-derived CD11b+ immune cells are decreased while CD3+ T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4+ T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD. Significance statement Immune cells and cytokines perform specialized functions inside and outside the brain to maintain optimal brain health; but the extent to which their activities change in response to neuronal dysfunction and degeneration is not well understood. Our findings indicate that neutralization of sTNF reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4+ Tcells. In addition, impaired long-term potentiation (LTP) was rescued by XPro1595 in association with decreased hippocampal Aβ plaques. Selective targeting of sTNF holds translational potential to modulate brain immune cell infiltration, dampen neuroinflammation, and prevent or delay neuronal dysfunction in AD.

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“…Further, studies find that the aged rats treated with TNF receptor 1 (TNFR1) signaling blockers-XPro1595 shows improved spatial memory and increased protein levels for the GluR1 type glutamate receptor in hippocampal CA1 neurons (Sama et al, 2012).…”

Section: J U S T a C C E P T E Dmentioning

confidence: 99%

Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction

Liu

Dai

et al. 2015

Stress

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Chronic stress is considered to be a major risk factor in the development of psychopathological syndromes in humans. Cognitive impairments and long-term potentiation (LTP) impairments are increasingly recognized as major components of depression, anxiety disorders and other stress-related chronic psychological illnesses. It seems timely to systematically study the potentially underlying neurobiological mechanisms of altered cognitive and synaptic plasticity in the course of chronic stress. In the present study, a rat model of chronic unpredictable stress (CUS) induced a cognitive impairment in spatial memory in the Morris water maze (MWM) test and a hippocampal LTP impairment. CUS also induced hippocampal microglial activation and attenuated phosphorylation of glutamate receptor 1 (GluR1 or GluA1). Moreover, chronic treatment with the selective microglial activation blocker, minocycline (120 mg/kg per day), beginning 3 d before CUS treatment and continuing through the behavioral testing period, prevented the CUS-induced impairments of spatial memory and LTP induction. Additional studies showed that minocycline-induced inhibition of microglia activation was associated with increased phosphorylation of GluR1. These results suggest that hippocampal microglial activation modulates the level of GluR1 phosphorylation and might play a causal role in CUS-induced cognitive and LTP disturbances.

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Inhibition of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations and Ca2+ Dysregulation in Aged Rats

Cited by 51 publications

References 94 publications

Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction

Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction

Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice

Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction

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