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.
BACKGROUND
Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.


METHODS
The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ(1-42) challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide.


RESULTS
3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with A(β1-42) 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.


CONCLUSIONS
Our 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.
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
David
D
Tweedie
Ryan A
RA
Ferguson
Kelly
K
Fishman
Kathryn A
KA
Frankola
Henriette
H
Van Praag
Harold W
HW
Holloway
Weiming
W
Luo
Yazhou
Y
Li
Luca
L
Caracciolo
Isabella
I
Russo
Sergio
S
Barlati
Balmiki
B
Ray
Debomoy K
DK
Lahiri
Francesca
F
Bosetti
Nigel H
NH
Greig
Susanna
S
Rosi
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D011916:Rats, Inbred F344; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*
C562075:3,6'-dithiothalidomide; D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide