Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by an excessive inflammatory response and impaired memory retrieval, including spatial memory, recognition memory, and emotional memory. Acquisition and retrieval of fear memory help one avoid dangers and natural threats. Thus, it is crucial for survival. AD patients with impaired retrieval of fear memory are vulnerable to dangerous conditions. Excessive expression of inflammatory markers is known to impede synaptic transmission and reduce the efficiency of memory retrieval. In wild-type mice, reducing inflammation response can improve fear memory retrieval; however, this effect of this approach is not yet investigated in 3xTg-AD model mice. To date, no satisfactory drug or treatment can attenuate the symptoms of AD despite numerous efforts. In the past few years, the direction of therapeutic drug development for AD has been shifted to natural compounds with anti-inflammatory effect. In the present study, we demonstrate that the compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) is effective in enhancing fear memory retrieval of wild-type and 3xTg-AD mice by reducing the expression of TNF-α, COX-2, and iNOS. We also found that 4-PSB-2 helps increase dendritic spine density, postsynaptic density protein-95 (PSD-95) expression, and long-term potentiation (LTP) in the hippocampus of 3xTg-AD mice. Our study indicates that 4-PSB-2 may be developed as a promising therapeutic compound for treating fear memory impairment of AD patients.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder known to involve neuronal inflammation (Newcombe et al, 2018) and impaired memory retrieval, including episodic memory, recognition memory, spatial memory (Serrano-Pozo et al, 2011; Wahl et al, 2017), and fearful and traumatic memory (Hamann et al, 2002)
We report that 4-(phenylsulfanyl) butan-2-one (4-PSB-2) significantly rescues the impairment of fear memory retrieval in 3xTg-AD mice and increases dendritic spine density and long-term potentiation (LTP) through the suppression of several inflammation markers in the basolateral amygdala (BLA) and hippocampus (Graphical Abstract), in the CA3region
Studies on AD patients have confirmed that atrophy (Basso et al, 2006) and functional disconnectivity (Ortner et al, 2016) of the hippocampus and BLA are associated with memory decline (Basso et al, 2006; Ortner et al, 2016)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder known to involve neuronal inflammation (Newcombe et al, 2018) and impaired memory retrieval, including episodic memory, recognition memory, spatial memory (Serrano-Pozo et al, 2011; Wahl et al, 2017), and fearful and traumatic memory (Hamann et al, 2002). We are the first to report that 4-PSB-2 acts as memory enhancer and anti-inflammatory compound, which can reverse impairments in fear memory retrieval in 3xTg-AD mice without changing Aβ levels. 4-PSB-2 reduces the expression of several inflammatory markers including TNF-α, COX-2, and iNOS, increases PSD-95 expression in the hippocampus, and improves synaptic dysfunction in 3xTg-AD mice, which may account for its effect in improving fear memory retrieval. An excessive inflammatory response is known to associate with impairments of working memory, remote memory stabilization, and spatial memory in AD (Murray et al, 2012; Wang et al, 2014; Mariani et al, 2017; Scuderi et al, 2018); its relationship with defective fear memory of AD is not clear yet
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