Administration of NaHS Attenuates Footshock-Induced Pathologies and Emotional and Cognitive Dysfunction in Triple Transgenic Alzheimer's Mice.

Hei-Jen Huang,Shu-Ling Chen,Hsiu Mei Hsieh-Li

doi:10.3389/fnbeh.2015.00312

Abstract

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and neuropsychiatric symptoms. Increasing evidence indicates that environmental risk factors in young adults may accelerate cognitive loss in AD and that Hydrogen Sulfide (H2S) may represent an innovative treatment to slow the progression of AD. Therefore, the aim of this study was to evaluate the effects of NaHS, an H2S donor, in a triple transgenic AD mouse model (3×Tg-AD) under footshock with situational reminders (SRs). Inescapable footshock with SRs induced anxiety and cognitive dysfunction as well as a decrease in the levels of plasma H2S and GSH and an increase in IL-6 levels in 3×Tg-AD mice. Under footshock with SR stimulus, amyloid deposition, tau protein hyperphosphorylation, and microgliosis were highly increased in the stress-responsive brain structures, including the hippocampus and amygdala, of the AD mice. Oxidative stress, inflammatory response, and β-site APP cleaving enzyme 1 (BACE1) levels were also increased, and the level of inactivated glycogen synthase kinase-3β (GSK3β) (pSer9) was decreased in the hippocampi of AD mice subjected to footshock with SRs. Furthermore, the numbers of cholinergic neurons in the medial septum/diagonal band of Broca (MS/DB) and noradrenergic neurons in the locus coeruleus (LC) were also decreased in the 3×Tg-AD mice under footshock with SRs. These biochemical hallmarks and pathological presentations were all alleviated by the semi-acute administration of NaHS in the AD mice. Together, these findings suggest that footshock with SRs induces the impairment of spatial cognition and emotion, which involve pathological changes in the peripheral and central systems, including the hippocampus, MS/DB, LC, and BLA, and that the administration of NaHS may be a candidate strategy to ameliorate the progression of neurodegeneration.

Highlights

Alzheimer’s disease (AD) is characterized by neuropsychological symptoms such as anxiety, depression and progressive cognitive deficits along with the deposition of extracellular plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein
Aβ40 (p < 0.001; Figure 4 and Table 2), Aβ42 (p < 0.001; Figure 2 and Table 2), and pS202 Tau (p < 0.001; Figure 4 and Table 2) were significantly lower in the basolateral nucleus of amygdala (BLA) in the footshock/NaHS group than in the footshock/saline group. These results indicate that amyloid deposition and phosphorylated tau protein levels were increased in the footshock-treated mice, whereas semiacute treatment with NaHS attenuated the footshock-induced pathological changes in the BLA in 3×Tg-AD mice
In vivo studies indicated that footshock with situational reminders (SRs) induced the impairment of spatial cognition and emotion, which are involved in peripheral and central systemic deficits including the hippocampus, medial septum/diagonal band of Broca (MS/DB), locus coeruleus (LC), and amygdala regions, whereas emotional and cognitive dysfunction were attenuated by semi-acute treatment with NaHS through targeting multiple pathogenic cascade in the 3×Tg-AD mice

Summary

Introduction

Alzheimer’s disease (AD) is characterized by neuropsychological symptoms such as anxiety, depression and progressive cognitive deficits along with the deposition of extracellular plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. A recent study suggests that psychiatric symptoms such as Effect of NaHS on Footshock-Stimulated 3×Tg-AD Mice depression and anxiety increase the severity of cognitive deficits (Ringman et al, 2015). We previously demonstrated that anxiety induced by inescapable footshock stress associated with situational reminders (SRs) enhances the toxicity of oligomeric Aβ40 and increases the severity of cognitive decline in C57BL/6J mice (Huang et al, 2010). Chronic mild stress increases β-site APP cleaving enzyme 1 (BACE1) levels in the hippocampus of aged mice (O’Connor et al, 2008; Solas et al, 2013). Stress hormones such as glucocorticoids may interfere with the balance between total and phosphorylated tau (Liston and Gan, 2011). In this study, inescapable footshock with SRs was used to accelerate disease progression in 6-month-old male 3×Tg-AD mice

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