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

• Type of Material: Article
• Authors: Kathryn P. MacPherson, Emory University; Pradoldej Sompol, University of Kentucky; George T. Kannarkat, Emory University; Jianjun Chang, Emory University; Lindsey Sniffen, Emory University; Mary E. Wildner, Emory University; Christopher M. Norris, University of Kentucky; Malu Tansey, Emory University
• Language: English
• Date: 2017-06-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2017.02.010
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 102
• Start Page: 81
• End Page: 95
• Grant/Funding Information: Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.; This study was supported in part by the Emory ADRC P50 AG025688, the Alzheimer’s Drug Discovery Foundation (MGT), NIA/NIH 1RF1AG051514-01 (MGT), a pre-doctoral training grant in translational research in neurology 5 T32 NS007480-14 (KPM), and the Emory Multiplexed Immunoassay Core (EMIC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.
• Keywords: MICROGLIA; Alzheimer's disease; TUMOR-NECROSIS-FACTOR; Long-term potentiation; Science & Technology; ALZHEIMERS-DISEASE; PROGRESSION; INFLAMMATION; Neurosciences & Neurology; T-CELLS; XPro1595; MHCII; Soluble TNF; CENTRAL-NERVOUS-SYSTEM; Neuroinflammation; Life Sciences & Biomedicine; T cells; EXPRESSION; Neurosciences; Immune cell trafficking; PATHOLOGY; MOUSE MODEL; Macrophage
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Neuroscience

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+T cells. 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.