Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in...

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alzheimer's disease (AD) is linked to disrupted neuronal calcium (Ca2+) signaling.
• Stabilizing Ca2+ signaling may offer disease-modifying treatments for AD.
• Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump regulators show neuroprotective potential.

Purpose of the Study:

• To evaluate novel sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump positive allosteric regulators (PAMs) for Alzheimer's disease (AD) therapy.
• To assess the neuroprotective effects of SERCA PAMs in cellular and animal models of AD.
• To identify promising lead compounds for AD disease-modifying agents.

Main Methods:

• Assessed Ca2+ extraction rates in HEK293T cells.
• Analyzed dendritic spine morphology in hippocampal neurons under normal and amyloid-toxic conditions.
• Measured long-term potentiation in brain slices from 5xFAD transgenic mice.

Main Results:

• Several novel SERCA PAM compounds exhibited neuroprotective properties.
• The compound NDC-9009 demonstrated the most significant neuroprotective effects.
• SERCA PAMs modulated Ca2+ handling and neuronal structure in AD models.

Conclusions:

• The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is a viable therapeutic target for Alzheimer's disease (AD).
• NDC-9009 is a promising lead molecule for developing disease-modifying treatments for AD.
• Stabilizing neuronal Ca2+ signaling via SERCA modulation offers a potential strategy for AD intervention.