Abstract
Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer’s disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12–14 months of age. Chronic sodium selenate treatment efficiently reversed hippocampal-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippocampus of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.
Highlights
Alzheimer’s disease (AD) is characterized by progressive memory decline and emotional and neuropsychiatric symptoms associated with accumulation of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs)[1]
A recent review of sixty studies reveals only a limited number of environmental risk factors for dementia, including selenium[9], an inorganic element whose deficiency is associated with increased risk of developing AD10,29,30
These results suggest for the first time that reducing pathological tau with Se may be useful for the treatment of memory and neuropsychiatric symptoms in AD
Summary
Alzheimer’s disease (AD) is characterized by progressive memory decline and emotional and neuropsychiatric symptoms associated with accumulation of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs)[1]. Cognitive decline correlates better with progression of tau pathology in the hippocampus rather than amyloid plaques in neocortical regions[2]. These classical pathological hallmarks accumulate in the hippocampus and cortex of transgenic 3xTg-AD mice, which develop age-dependent hippocampal-dependent cognitive deficits and neuropsychiatric-like disturbances[3,4,5,6]. Targeting Aβ and phosphorylated tau ameliorate and/ or reverse memory and synaptic deficits in 3xTg-AD mice[7], it is still unclear whether targeting tau independently of Aβ may have therapeutic benefits on cognition and/or emotional symptoms at late AD stages. We investigated the effects of chronic dietary sodium selenate supplementation on both cognitive and neuropsychiatric-like domains, and studied the pathological mechanisms involved, in old 3xTg-AD mice
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