Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease
Shreaya Chakroborty1, Clark Briggs, Megan B Miller
1Department of Neuroscience, Rosalind Franklin University/The Chicago Medical School, North Chicago, IL, USA.
Plos One
|January 4, 2013
Summary
This study shows that dantrolene, an inhibitor of ryanodine receptors (RyR), normalizes calcium signaling and synaptic function in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Alzheimer's disease (AD) lacks effective treatments, with current therapies targeting late-stage pathology.
- Early synaptic dysfunction, driven by dysregulated calcium (Ca2+) homeostasis, is linked to cognitive decline in AD.
- Increased intracellular Ca2+ signaling via inositol triphosphate (IP3) and ryanodine receptors (RyR) is an early AD indicator.
Purpose of the Study:
- To investigate the potential of targeting ryanodine receptors (RyR) to stabilize early Alzheimer's disease (AD) pathogenesis.
- To evaluate the therapeutic efficacy of dantrolene, an RyR inhibitor, in preclinical AD mouse models.
Main Methods:
- Sub-chronic treatment of Alzheimer's disease (AD) mouse models with a novel dantrolene formulation.
- Utilized 2-photon Ca2+ imaging and patch clamp recordings to assess Ca2+ signaling and synaptic function.
- Measured RyR2 levels, synaptic transmission, synaptic plasticity, and amyloid-beta (Aβ) deposition.
Main Results:
- Dantrolene treatment normalized endoplasmic reticulum (ER) Ca2+ signaling in both early and late-stage AD mice.
- Elevated RyR2 levels, synaptic transmission, and synaptic plasticity were restored to control levels.
- Amyloid-beta (Aβ) deposition in the cortex and hippocampus was reduced following dantrolene administration.
Conclusions:
- Aberrant Ca2+ signaling plays a critical role in Alzheimer's disease (AD) pathophysiology.
- Targeting RyR with dantrolene offers a novel therapeutic strategy to preserve synaptic and cognitive function in early AD.
- Stabilizing early pathogenic mechanisms, such as RyR-mediated Ca2+ dysregulation, may prevent AD progression.
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