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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


Year of Publication:
Contact PI Name:
Malu G. Tansey
Contact PI Affiliation:
Emory University School of Medicine, Whitehead Biomedical Research Building., Atlanta, Georgia, USA
Kathryn P. MacPherson, Pradoldej Sompol, George T. Kannarkat, Jianjun Chang, Lindsey Sniffen, Mary E.Wildner, Christopher M. Norris
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Drug Discovery Foundation (ADDF)
National Institute of Neurological Disorders and Stroke (NINDS)
Emory Multiplexed Immunoassay Core
National Center for Advancing Translational Sciences (NCATS)
Study Goal and Principal Findings:

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, they 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. They 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Peptide
Therapeutic Agent:
Therapeutic Target:
Soluble Tumor Necrosis Factor (sTNF)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Dystrophic Neurites
beta Amyloid Deposits
Plasma-Interferon (IFN) gamma
Plasma-Interleukin-1 beta (IL-1 beta)
Interleukin 10 (IL-10)
Interleukin 12p70 (IL-12p70)
Chemokine C-X-C Motif Ligand 1 (CXCL1/mKC)
Interferon (IFN) gamma mRNA
Tumor Necrosis Factor Receptor 1 (TNFR1) mRNA
Interleukin 6 (IL-6)
Tumor Growth Factor beta (TGF beta)
Chemokine C-C Motif Ligand 2/Monocyte Chemoattractant Protein 1 (CCL2/MCP1)
Tumor Necrosis Factor alpha (TNF alpha)
Interferon (IFN) gamma
Interleukin 1 beta (IL-1 beta)
Brain-beta Amyloid Deposits
Cell Biology
Peripheral Blood Leukocytes
field Excitatory Postsynaptic Potential (fEPSP)
Drug Concentration-Serum
Drug Concentration-Brain