Engineered APP C-terminus Alters Its Native Transcript Dynamics in Differentiated SH-SY5Y-Derived Neurons

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) pathology involves amyloid precursor protein (APP) processing.
• APP fragments like AICD and CTF are linked to transcriptional regulation.
• The self-regulatory role of APP fragments on APP splicing and expression is not well understood.

Purpose of the Study:

• To investigate the self-regulatory potential of APP C-terminal fragments on endogenous APP expression and splicing.
• To determine if APP fragments can modulate native APP transcript variants.

Main Methods:

• Generated stable transgenic SH-SY5Y cell lines overexpressing various APP constructs.
• Differentiated cells into mature neuron-like cells over 24 days.
• Analyzed APP transcript variants and differential splicing patterns.

Main Results:

• Overexpression of APP fragments altered total APP levels and specific transcript variants (APPv3, APPv11) in differentiated neurons.
• Differential splicing patterns were confirmed via transcript fragment-size analysis.
• APP derivatives were shown to influence transcriptional regulation and alternative splicing of native APP.

Conclusions:

• APP fragments possess self-regulatory capabilities, modulating their own transcription and splicing.
• This self-regulatory complexity of APP provides new insights into AD pathogenesis.
• APP fragments may act as transcription modulators, suggesting novel therapeutic strategies for AD.