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Published on: March 22, 2016
Limiting RyR2 open time prevents Alzheimer's disease-related deficits in the 3xTG-AD mouse model
Yajing Liu1,2, Jinjing Yao1, Zhenpeng Song1
1Department of Physiology and Pharmacology, Cumming School of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada.
Abstract:
Increasing evidence suggests that Alzheimer's disease (AD) progression is driven by a vicious cycle of soluble β-amyloid (Aβ)-induced neuronal hyperactivity. Thus, breaking this vicious cycle by suppressing neuronal hyperactivity may represent a logical approach to stopping AD progression. In support of this, we have recently shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevented neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in a rapid, early onset AD mouse model (5xFAD). Here, we assessed the impact of limiting RyR2 open time on AD-related deficits in a relatively late occurring, slow developing AD mouse model (3xTG-AD) that bears more resemblance (compared to 5xFAD) to that of human AD. Using behavioral tests, long-term potentiation recordings, and Golgi and Nissl staining, we found that the RyR2-E4872Q mutation, which markedly shortens the open duration of the RyR2 channel, prevented learning and memory impairment, defective long-term potentiation, dendritic spine loss, and neuronal cell death in the 3xTG-AD mice. Furthermore, pharmacologically shortening the RyR2 open time with R-carvedilol rescued these AD-related deficits in 3xTG mice. Therefore, limiting RyR2 open time may offer a promising, neuronal hyperactivity-targeted anti-AD strategy.
Insights
Targeting neuronal hyperactivity in Alzheimer's disease (AD) by limiting ryanodine receptor 2 (RyR2) open time shows promise. This approach prevented cognitive decline and neuronal death in a mouse model, suggesting a new AD therapeutic strategy.
Area of Science:
- Neuroscience
- Pharmacology
- Gerontology
Background:
- Alzheimer's disease (AD) progression is linked to a cycle of amyloid-beta (Aβ) induced neuronal hyperactivity.
- Suppressing neuronal hyperactivity is a potential strategy to halt AD progression.
Purpose of the Study:
- To investigate the therapeutic potential of limiting ryanodine receptor 2 (RyR2) open time in a late-onset Alzheimer's disease mouse model (3xTG-AD).
- To assess the impact of RyR2 modulation on cognitive deficits, synaptic plasticity, and neuronal survival in the 3xTG-AD model.
Main Methods:
- Utilized the 3xTG-AD mouse model, which mimics human AD progression more closely than early-onset models.
- Employed behavioral tests, electrophysiological recordings (long-term potentiation), and histological analyses (Golgi and Nissl staining).
- Investigated both genetic (RyR2-E4872Q mutation) and pharmacological (R-carvedilol) interventions to shorten RyR2 open time.
Main Results:
- The RyR2-E4872Q mutation prevented learning and memory impairments in 3xTG-AD mice.
- RyR2 modulation rescued defective long-term potentiation, reduced dendritic spine loss, and prevented neuronal cell death.
- Pharmacological inhibition using R-carvedilol also ameliorated AD-related deficits in the 3xTG-AD model.
Conclusions:
- Limiting RyR2 open time is a viable strategy to counteract neuronal hyperactivity in Alzheimer's disease.
- This approach offers a promising therapeutic avenue targeting a key pathological mechanism in AD.
- RyR2 modulation represents a potential disease-modifying therapy for Alzheimer's disease.
