3,6'-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit

Abstract

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 (AÃ)1-42 peptide. Seven days after Aβ1-42 injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four weeks after Aβ1-42 peptide injection, elevated numbers of surviving 5-bromo-2'-deoxyuridine cells and newly formed neurons were detected. Treatment with 3,6'-dithiothalidomide attenuated these Aβ1-42 provoked effects. Our data indicate that although treatment with 3,6'-dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by Aβ1-42-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 Aβ1-42 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. TNF-α inhibition attenuates memory impairment and augmented hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammationNeuroinflammation has a critical role in the degeneration of hippocampal neurons, cognitive impairment, and altered neurogenesis. We investigated whether TNF-α is involved in the modulation of the neurogenic niche and memory tasks following Aβ1-42-induced inflammation using the novel 3,6'-dithiothalidomide TNF-α inhibitor. 3,6'-dithiothalidomide attenuated neuroinflammation, memory impairment, and the increase in hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammation. © Published 2012. This article is a US Government work and is in the public domain in the USA.