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Updated: Aug 12, 2025
06:23
Visualizing Axonal Growth Cone Collapse and Early Amyloid β Effects in Cultured Mouse Neurons
Published on: October 30, 2018
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The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment
Fulin Ma1,2, Himanshu Akolkar1, Jianquan Xu3
1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
Summary
Elevated amyloid precursor protein (APP) levels, triggered by neuronal activity, alter axon initial segment structure and function. This APP effect, not beta-amyloid, is linked to Alzheimer's disease pathology.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The amyloid precursor protein (APP) is central to Alzheimer's disease (AD) pathogenesis, primarily as the source of β-amyloid (Aβ) peptides forming amyloid plaques.
- The normal physiological functions of full-length APP remain less understood compared to its role in Aβ production.
Purpose of the Study:
- To investigate the non-amyloidogenic functions of APP, particularly its response to neuronal activity and its impact on neuronal structure.
- To explore the potential role of full-length APP in the cellular mechanisms underlying Alzheimer's disease.
Main Methods:
- Studied the effect of glutamate stimulation on APP gene expression in mouse and human neurons.
- Analyzed changes in the axon initial segment (AIS) structure and neuronal activity using techniques like GCaMP8f Ca2+ reporter.
- Investigated the cell-autonomous effects of APP and the influence of familial AD mutations (APP Swe).
- Examined the association of APP with AIS scaffolding proteins (Ankyrin G, βIV-spectrin) in AD models and human samples.
Main Results:
- Glutamate stimulation rapidly increases APP gene expression and protein levels.
- Elevated APP protein shortens the AIS and shifts it away from the cell body, leading to decreased neuronal activity.
- APP's effects on the AIS are cell-autonomous; exogenous Aβ has no impact.
- Familial AD mutations in APP exacerbate AIS alterations.
- APP physically associates with AIS scaffolding proteins, an association heightened in AD brains and models.
- Increased APP levels and shortened AIS are observed in human sporadic AD and an AD mouse model.
Conclusions:
- Full-length APP plays a significant role in regulating neuronal structure and function, independent of Aβ production.
- APP's modulation of the AIS represents a novel mechanism potentially contributing to synaptic dysfunction and cognitive decline in Alzheimer's disease.
- These findings necessitate a re-evaluation of APP's multifaceted role in both normal brain function and AD pathogenesis.
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