Abstract
We have previously reported that primary hippocampal neurons exposed to synaptotoxic amyloid beta oligomers (AβOs), which are likely causative agents of Alzheimer’s disease (AD), exhibit abnormal Ca2+ signals, mitochondrial dysfunction and defective structural plasticity. Additionally, AβOs-exposed neurons exhibit a decrease in the protein content of type-2 ryanodine receptor (RyR2) Ca2+ channels, which exert critical roles in hippocampal synaptic plasticity and spatial memory processes. The antioxidant N-acetylcysteine (NAC) prevents these deleterious effects of AβOs in vitro. The main contribution of the present work is to show that AβOs injections directly into the hippocampus, by engaging oxidation-mediated reversible pathways significantly decreased RyR2 protein content but increased single RyR2 channel activation by Ca2+ and caused considerable spatial memory deficits. AβOs injections into the CA3 hippocampal region impaired rat performance in the Oasis maze spatial memory task, decreased hippocampal glutathione levels and overall content of plasticity-related proteins (c-Fos, Arc, and RyR2) and increased ERK1/2 phosphorylation. In contrast, in hippocampus-derived mitochondria-associated membranes (MAM) AβOs injections increased RyR2 levels. Rats fed with NAC for 3-weeks prior to AβOs injections displayed comparable redox potential, RyR2 and Arc protein contents, similar ERK1/2 phosphorylation and RyR2 single channel activation by Ca2+ as saline-injected (control) rats. NAC-fed rats subsequently injected with AβOs displayed the same behavior in the spatial memory task as control rats. Based on the present in vivo results, we propose that redox-sensitive neuronal RyR2 channels partake in the mechanism underlying AβOs-induced memory disruption in rodents.
Highlights
The pathological hallmarks of Alzheimer’s disease (AD) – the most common neurodegenerative disorder and the leading cause of dementia in the elderly – are the presence of amyloid plaques and neurofibrillary tangles, which presumably arise from excessive accumulation and aggregation of amyloid β (Aβ) peptides in the brain of affected individuals
After finishing the injections, Aβ oligomers (AβOs)-injected rats displayed lower hit rates (Figure 1A, left panel), defined as the number of times the rat found the reward over the 15 trials, with significantly lower average values compared to the controls (Figure 1A, right panel)
The average latency to find the reward in sessions 2 to 6 was significantly lower in the control group (Figure 1B, left panel) compared to the group injected with AβOs (Figure 1B, right panel)
Summary
The pathological hallmarks of Alzheimer’s disease (AD) – the most common neurodegenerative disorder and the leading cause of dementia in the elderly – are the presence of amyloid plaques and neurofibrillary tangles, which presumably arise from excessive accumulation and aggregation of amyloid β (Aβ) peptides in the brain of affected individuals. Before the emergence of plaques and/or neurofibrillary tangles, independent yet intersecting age-related pathologies have been proposed to cause AD (Tse and Herrup, 2017), including Ca2+ dyshomeostasis, excitotoxicity, mitochondrial dysfunction, increased contacts between the ER and the mitochondria, neuroinflammation and alterations in lipid metabolism (Brito-Moreira et al, 2011; Paula-Lima et al, 2013; Area-Gomez et al, 2018; Olloquequi et al, 2018; Popugaeva et al, 2018). It remains to be established how these early defects relate to the emergence and progression of AD. AβOs trigger reactive oxygen/nitrogen species (ROS/RNS) generation (SanMartin et al, 2017; Munoz et al, 2018), decrease neuronal glutathione (GSH) levels, inhibit the activities of antioxidant enzymes and impair mitochondrial function, resulting in neuronal oxidative stress (Turunc Bayrakdar et al, 2014) and non-resolving inflammatory response (Frozza et al, 2018)
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