Limiting RyR2 open time prevents Alzheimer's disease‐related deficits in the 3xTG‐AD mouse model
| Autor: | Zhenpeng Song, Wenting Guo, Jinjing Yao, Thomas G. Back, S.R. Wayne Chen, Bo Sun, Yajing Liu, John Paul Estillore, Jinhong Wei |
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| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Dendritic spine Mice Transgenic medicine.disease_cause Ryanodine receptor 2 Mice 03 medical and health sciences Cellular and Molecular Neuroscience symbols.namesake 0302 clinical medicine Alzheimer Disease medicine Animals Memory impairment 030304 developmental biology 0303 health sciences Mutation Amyloid beta-Peptides business.industry Ryanodine Receptor Calcium Release Channel Long-term potentiation Golgi apparatus Disease Models Animal Nissl body symbols business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroscience Research. 99:2906-2921 |
| ISSN: | 1097-4547 0360-4012 |
| DOI: | 10.1002/jnr.24936 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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