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Neuroprotective properties of anti-apoptotic BCL-2 proteins in 5xFAD mouse model of Alzheimer’s disease

Summary

Scientists studied how Bcl-2 proteins might protect the brain from Alzheimer’s disease by controlling calcium levels in nerve cells. They injected modified Bcl-2 proteins into the brains of mice engineered to develop Alzheimer’s symptoms and found that these proteins helped preserve the connections between nerve cells and reduced harmful amyloid plaque buildup. A special version of Bcl-2 that worked primarily on one type of calcium channel was surprisingly most effective at reducing amyloid plaques, suggesting this specific mechanism could be important for treating Alzheimer’s disease.

Background

Alzheimer’s disease is characterized by dysregulation of intracellular Ca2+ signaling in neurons, particularly increased Ca2+ release from endoplasmic reticulum-located channels. Bcl-2 proteins are known for anti-apoptotic properties and can inhibit Ca2+ flux through IP3Rs and RyRs. This study examines whether Bcl-2 expression can normalize dysregulated Ca2+ signaling in a 5xFAD mouse model of AD.

Objective

To investigate whether overexpression of Bcl-2 proteins can normalize dysregulated Ca2+ signaling and prevent or slow AD progression in 5xFAD mice. The study specifically examines wild-type Bcl-2 and a Bcl-2 K17D mutant with impaired IP3R binding to determine the importance of IP3R1 association in neuroprotection.

Results

Bcl-2 and Bcl-2 K17D both bind to RyR2 with equal potency but Bcl-2 K17D shows reduced binding to IP3R1. Both proteins displayed synaptoprotective effects increasing mushroom spines and reducing dendritic spine loss in 5xFAD mice. Notably, only Bcl-2 K17D significantly reduced amyloid plaque accumulation, suggesting RyR2 inhibition without IP3R1 inhibition may be critical for amyloid protection.

Conclusion

Bcl-2-based strategies show neuroprotective potential in AD models with complex mechanisms. While wild-type Bcl-2 provides superior synaptoprotection through dual IP3R/RyR inhibition, the Bcl-2 K17D mutant’s selective RyR2 inhibition offers superior amyloid-protective effects. The findings warrant further investigation of RyR2 as a therapeutic target in AD, though additional research is needed to fully elucidate the underlying mechanisms.
  • Published in:IBRO Neuroscience Reports,
  • Study Type:Experimental Research,
  • Source: PMID: 36926591
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