Year-end Sale % OFF 
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia
Hyperexcitability of Tg2576 granule cells (GCs) and impaired pattern separation in Tg2576 mice are restored by antioxidant treatment We previously reported that mitochondrial reactive oxygen species (ROS) production is increased in Tg2576 dentate gyrus (DG) at the age of 1- to 2-months, causing depolarization of mitochondrial membrane potential and impairment of Ca2+ uptake int mitochondria
It was demonstrated that mitochondrial dysfunctions such as increased ROS production, partial depolarization of mitochondrial potential, and impaired Ca2+ uptake occurred in dentate GCs of 1 ~ 2-month-old Tg2576 mice, leading to the deficits in mitochondria-dependent short-term plasticity at the mossy fiber-Cornu Ammonis 3 area of hippocampus (CA3) synapses
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. All three hippocampal pathways have been associated with learning and memory, MF-CA3 projection has been implicated in cognitive function, including novelty detection, pattern completion and pattern separation [17, 18]. Synaptic activity in the DG/CA3 network was proposed as an early target of amyloid pathology that leads to impaired pattern separation and episodic memory loss [21]. Impaired synaptic plasticity in MF-CA3 synapses at an early stage in AD model mice was reported [22, 23]. It remains to be elucidated how alteration of intrinsic excitability contributes to impaired DG/ CA3 network underlying AD-associated cognitive deficit
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
