Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Primary cilia are crucial sensory organelles in neurons, involved in signaling pathways like Sonic hedgehog (Shh).
• Cilia dysfunction causes ciliopathies, often associated with cognitive impairment, similar to Alzheimer's disease (AD).
• AD is characterized by Amyloid-β (Aβ) accumulation, derived from amyloid precursor protein (APP).

Purpose of the Study:

• To investigate the impact of Aβ on primary cilia structure.
• To determine if Aβ affects the Shh signaling pathway.

Main Methods:

• Utilized in vitro cell-based assays with NIH3T3 and HeLa cells.
• Employed fluorescent confocal microscopy to analyze cilia structure.
• Assessed Shh signaling via luciferase activity and Aβ effects using naturally secreted and synthetic Aβ.

Main Results:

• Amyloid precursor protein (APP) was found to localize to primary cilia.
• Aβ treatment led to distorted primary cilia structure.
• Aβ treatment was shown to interrupt canonical Shh signal transduction.

Conclusions:

• Aβ can alter primary cilia structure, potentially affecting neuronal cilia in AD.
• Aβ impairs the Shh signaling pathway.
• Findings highlight primary cilia and Shh signaling as potential therapeutic targets for AD.