Selenomethionine Ameliorates Neuropathology in the Olfactory Bulb of a Triple Transgenic Mouse Model of Alzheimer’s Disease

Abstract

Olfactory dysfunction is an early and common symptom in Alzheimer′s disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aβ and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aβ and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD). In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB) of 3× Tg-AD mice was investigated. The administration of Se-Met effectively decreased the production and deposition of Aβ by inhibiting β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-regulated amyloid precursor protein (APP) processing and reduced the level of total tau and phosphorylated tau, which depended on depressing the activity and expression of glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5). Meanwhile, Se-Met reduced glial activation, relieved neuroinflammation and attenuated neuronal cell death in the OB of AD mice. So Se-Met could improve pathologic changes of AD in the OB, which further demonstrated the potential therapeutic effect of Se-Met in AD.

Transcriptomic Insights into the Response of the Olfactory Bulb to Selenium Treatment in a Mouse Model of Alzheimer’s Disease

“…It is also reported that the expression level of Lrg1 is correlated with inflammation [62]. Therefore, a significant decrease in the Lrg1 expression level after Se-Met treatment of 3xTg AD mice confirmed that Se-Met has a role in alleviating the inflammation of AD, which agrees with our previous results [9,10].…”

“…Moreover, olfactory deficits also occurred before the clinical onset of cognitive deficits and coincided with AD pathology [16]. In our previous study [10], we found that, in addition to an improvement in cognitive ability, Se-Met treatment also induced a significant neuropathological improvement in the OB of 7-month-old 3×Tg-AD mice. Thus, AD-associated pathology in OB is also sensitive to pharmacological interventions, such as for those in the cortex and hippocampus [13].…”

“…It has been suggested that the olfactory bulb could be a starting point of pathology in AD [8]. In our previous study, we showed that selenomethionine (Se-Met), a major form of selenium in organisms, effectively increased oxidation resistance as well as reduced the production and deposition of Aβ and tau hyperphosphorylation in the hippocampus, cortex, and also the olfactory bulb of a triple transgenic mouse model of AD (3×Tg-AD) [9,10]. In addition, we determined the selenium levels in the tissues and organs of AD mice before and after treatment with Se-Met, and found that the level of selenium in brain tissue and olfactory bulb tissue increased significantly, indicating that selenium plays a biological role in the process of Se-Met treatment of AD mice [11].…”

Ocimum basilicum (Basil) Modulates Apoptosis and Neurogenesis in Olfactory Pulp of Mice Exposed to Chronic Unpredictable Mild Stress

“…The laminar organization of olfactory bulb combines a unique neuronal morphology and complex synaptic connections which play a basic role in smell perception and modify the response of the output neurons for sharp tuning of a given odor ( 29 ). Olfactory dysfunction is considered a premotor sign of neurodegeneration that appears early in the degenerative process as in Alzheimer disease and Parkinson disease ( 30 , 31 ). Moreover, the olfactory bulbectomy of rats has been validated as a model of depression over the past 30 years, suggesting a close relationship between MOB and depression ( 15 – 17 ).…”

Olfactory dysfunction in the 3xTg-AD model of Alzheimer’s disease

“…In this later study they focused specifically on changes in the OB of the 3xTg-AD mice. Using Western blotting, they found that Se-Met-treated mice had lower levels of BACE1 (β-site APP cleaving enzyme 1), APP, and phosphorylated tau ( Zhang et al, 2016 ). H&E and immunohistochemistry showed reduced Aβ in all layers of OB.…”