The 4-(Phenylsulfanyl) butan-2-one Improves Impaired Fear Memory Retrieval and Reduces Excessive Inflammatory Response in Triple Transgenic Alzheimer's Disease Mice

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.

Effect of Vitamin D Supplementation on the Progression of Alzheimer’s Disease in Rats: A Mechanistic Approach

“…Our results are consistent with another study showing a decrease in in ammatory mediators (IL-1β, IL-6, NF-κβ) in the hippocampal regions of the brain due to vitamin D supplementation (Farhangi et al 2017). The decrease in the in ammatory mediators may also inhibit the over-activation of hippocampal cells and thus can reduce the accumulation of Aβ plaques (Varinthra et al 2021).…”

“…Fear conditioning response is a hippocampus and amygdala dependent memory function. Loss of functional connectivity between the hippocampus and amygdala may be responsible for memory loss in the early stages of AD AD (Hamann et al 2002;Varinthra et al 2021). The rats injected with scopolamine indicated a reduction in fear memory retrieval (decrease in freezing time), while treatment with vitamin D or donepezil signi cantly improved the contextual as well as conditioned fear memory retrieval.…”

“…These proin ammatory cytokines can mediate neurotoxicity leading to AD (Wang et al 2015). These mediators can also reduce the endocytosis and phagocytosis of Aβ proteins by the microglial cells (Varinthra et al 2021). Further, NF-κβ is reported to be important in maintaining learning, memory as well as synaptic plasticity.…”

Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

“…Appropriate fear memory in response to potential danger in the environment is crucial for animal survival, while abnormal fear memory is implicated in several mental disorders (Nielen et al, 2009;Bowers and Ressler, 2015;Taylor and Torregrossa, 2015;Varinthra et al, 2021). The BLA is an obvious region of interest in view of its central role in the fear circuitry, mediating both fear learning and its expression (Luyck et al, 2020).…”

“…Learning to identify and respond to threats in the environment is essential for animal survival. Abnormal fear memory is a hallmark of many neuropsychiatric disorders, including Alzheimer's disease (Varinthra et al, 2021), obsessive-compulsive disorder (Nielen et al, 2009), posttraumatic stress disorder (Bowers and Ressler, 2015), and drug addiction (Taylor and Torregrossa, 2015). In mammals, it is well established that the basolateral amygdala (BLA) plays a central role in the formation and retention of fear memory (Davis and Whalen, 2001;Janak and Tye, 2015;Marek et al, 2019).…”