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Tumor necrosis factor-α synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease


Year of Publication:
Contact PI Name:
Greig H. Nigel
Contact PI Affiliation:
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
David Tweedie, Ryan A Ferguson, Kelly Fishman, Kathryn A Frankola, Henriette Van Praag, Harold W Holloway, Weiming Luo, Yazhou Li, Luca Caracciolo, Isabella Russo, Sergio Barlati, Balmiki Ray, Debomoy K Lahiri, Francesca Bosetti, Susanna Rosi
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
Intramural Research Program of the National Institute on Aging
National Cancer Institute (NCI)
Study Goal and Principal Findings:

The goal of this study was to further define the role of TNF alpha in  neuroinflammation, neuronal dysfunction and cognitive impairment. This was determined by testing the efficacy of a TNF alpha synthesis lowering agent  3,6′-dithiothalidomide on neuroinflammation-induced cognitive impairment exhibited in the 3x Tg AD mouse model, mice challenged with Aβ1–42 peptide,  and LPS-challenged rats. 6′-Dithiothaliodmide treatment lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.  The data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Tumor Necrosis Factor alpha (TNF alpha)

Animal Model

Model Information:
Model Type:
beta Amyloid Peptide Injection
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Fischer 344
Model Type:
Strain/Genetic Background:
Not Reported
Animal Model Notes:
Refer to for characterization of transgenic rats.

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
Morris Water Maze
Open Field Test
beta Amyloid Deposits
Tumor Necrosis Factor alpha (TNF alpha)
Amyloid Precursor Protein (APP)
Synaptic Proteins
Activity-Regulated Cytoskeleton-Associated Protein (Arc)
Brain-beta Amyloid Peptide 42
Activated Microglia
Activated Astrocytes
Target Engagement (Reduction Tumor Necrosis Factor alpha-Plasma)