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Updated: May 11, 2026
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Biochemical Purification and Proteomic Characterization of Amyloid Fibril Cores from the Brain
Published on: April 28, 2022
The amyloid precursor protein: a biochemical enigma in brain development, function and disease
Natalia N Nalivaeva1, Anthony J Turner
1School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. n.n.nalivaeva@leeds.ac.uk
FEBS Letters
|May 21, 2013
Summary
The amyloid cascade hypothesis for Alzheimer disease (AD) needs reevaluation. The amyloid precursor protein (APP) and its cleaved intracellular domain (AICD) play crucial roles in gene regulation, offering new therapeutic targets for neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The amyloid cascade hypothesis has dominated Alzheimer disease (AD) research for two decades, focusing on amyloid-β peptide (Aβ) and amyloid precursor protein (APP).
- Despite extensive research, the therapeutic translation of this hypothesis has yielded limited success, prompting a re-examination of APP's role.
- APP metabolites, beyond Aβ, possess distinct physiological functions, including transcriptional regulation by the cleaved intracellular domain (AICD).
Purpose of the Study:
- To explore the physiological and pathological functions of APP and its metabolites.
- To investigate the gene regulatory network involving APP, AICD, and related enzymes.
- To identify novel therapeutic strategies for neurodegenerative diseases, including AD, by understanding APP's broader roles.
Main Methods:
- Analysis of APP processing pathways and its splice isoforms (APP695, APP751, APP770).
- Investigation of the transcriptional regulation mediated by the APP intracellular domain (AICD), including its promoter binding.
- Review of existing literature on APP's functions in brain development, synaptic plasticity, and neuroprotection.
Main Results:
- APP695 is the primary neuronal isoform, preferentially generating Aβ and transcriptionally active AICD via the amyloidogenic pathway.
- AICD directly regulates the expression of key genes, including APP itself, BACE-1, and neprilysin.
- Secreted forms of APP demonstrate neuroprotective properties, highlighting diverse physiological roles.
Conclusions:
- The amyloid cascade hypothesis may be incomplete; APP and its metabolites, particularly AICD, have significant, underappreciated roles in gene regulation.
- Understanding the full spectrum of APP's physiological and pathological functions and its regulatory network is crucial for developing effective neurodegenerative disease therapies.
- Targeting APP's metabolic and gene regulatory pathways presents promising new avenues for therapeutic intervention in AD and other neurodegenerative conditions.
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