3,6'-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit.
Evidence indicates altered neurogenesis in neurodegenerative diseases associated with inflammation, including Alzheimer's disease (AD). Neuroinflammation and its propagation have a critical role in the degeneration of hippocampal neurons, cognitive impairment, and altered neurogenesis. Particularly, tumor necrosis factor (TNF)-α plays a central role in initiating and regulating the cytokine cascade during an inflammatory response and is up-regulated in brain of AD patients. In this study, we investigated the effects of a novel thalidomide-based TNF-α lowering drug, 3,6'-dithiothalidomide, on hippocampal progenitor cell proliferation, neurogenesis and, memory tasks after intracerebroventricular injection of β-amyloid (Aß)(1-42) peptide. Seven days after Aβ(1-42) injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four weeks after Aβ(1-42) peptide injection, elevated numbers of surviving 5-bromo-2'-deoxyuridine cells and newly formed neurons were detected. Treatment with 3,6'-dithiothalidomide attenuated these Aβ(1-42) provoked effects. Our data indicate that although treatment with 3,6'-dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by Aβ(1-42) -induced neuroinflammation, the drug prevented memory deficits associated with increased numbers of activated microglial cells and inflammatory response. Therefore, 3,6'-dithiothalidomide treatment likely reduced neuronal tissue damage induced by neuroinflammation following Aβ(1-42) injection. Understanding the modulation of neurogenesis, and its relationship with memory function could open new therapeutic interventions for AD and other neurodegenerative disorders with an inflammatory component.
Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, NIH, Bethesda, MD, USA.
Isabella
I
Russo
Luca
L
Caracciolo
David
D
Tweedie
Sang-Ho
SH
Choi
Nigel H
NH
Greig
Sergio
S
Barlati
Francesca
F
Bosetti
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
C562075:3,6'-dithiothalidomide; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D013792:Thalidomide