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

Abstract

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.

Spinal motor circuit synaptic plasticity after peripheral nerve injury depends on microglia activation and a CCR2 mechanism

“…8 J, K ). The numbers and proportions of each cell population in blood samples from Ccr2 RFP/ϩ heterozygous animals were similar to previously published materials, suggesting effective detection and discrimination (MacPherson et al, 2017). CCR2-RFP fluorescence was somewhat stronger in Ccr2 RFP/ RFP KO mice (Fig.…”

“…Cells were suspended in 1ϫ HBSS (Hank's Balance Salt Solution without calcium, Invitrogen), and 1 million cells were stained for flow cytometry. Methods are as previously described in more detail (MacPherson et al, 2017).…”

“…Samples were run on an LSRII Flow Cytometer (BD Biosciences). The antibody panel was extensively validated by antibody titrations using blood and spleen (MacPherson et al, 2017). Background levels were set using antibody isotypes and FMO (fluorescence minus one) controls.…”

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

“…Importantly, significant differences in slope between treatment groups indicate that XPro1595 treatment dampened inflammation. Systemic dosing of XPro1595 achieved plasma levels of 10-117μg/mL, CSF levels of 3-83 ng/mL, and cortex levels of 1-38 ng/mL in animals that received the drug, while vehicle animals were below detectable levels or below the lowest levels found in XPro1595-treated animals (Figure S5), consistent with previous published studies in rodents (Barnum et al, 2014;MacPherson et al, 2017).…”

Counteracting the effects of TNF receptor‐1 has therapeutic potential in Alzheimer's disease

“…Conversely, TNFR2 activation protects against glutamate‐induced excitotoxicity (Marchetti et al , ; Olmos & Llado, ). Moreover, it has been shown that selective inhibition of soluble TNF restores the synaptic dysfunction and long‐term potentiation impairment in 5XFAD mice (MacPherson et al , ). Further research is needed to address these possibilities in our established models.…”