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Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions
Fredrik Olsson1, Staffan Schmidt, Veit Althoff
1From the AstraZeneca iMED CNS/Pain, 15185 Södertälje, Sweden.
Abstract:
Processing of the amyloid precursor protein (APP) by γ-secretase results in generation of Aβ peptides of different lengths ranging from 51 to 30 residues. Accumulation of Aβ and in particular Aβ42 is enhanced by familial Alzheimer disease (FAD) causing mutations in APP and is believed to play a pivotal role. The molecular mechanism underlying normal Aβ production, the impact of FAD mutations on this process and how anti-amyloidogenic γ-secretase modulators (GSMs) cause a selective decrease in Aβ40 and Aβ42 and an increase in shorter Aβ peptides, however, is poorly understood. By using a combined immuno- and LC-MS-based assay we identify several major intermediates, i.e. 3- and 4-peptides that line up head to head across the entire APP transmembrane sequence from Aβ51 to Aβ31/Aβ30 and from Aβ49 to Aβ30/31. FAD APP mutations displayed a relative increase in 3- and 4-peptides from Aβ48 to Aβ38 compared with Aβ49 to Aβ37. These findings correlate with an increase in the Aβ42/40 ratio. GSMs caused a decrease in Aβ40 and Aβ42 and an increase in Aβ37 and Aβ38 paralleled by an increase of the intermediates Aβ40-38 and Aβ42-39. Collectively, these data provide a thorough characterization of all intermediate steps in Aβ production in native cell membranes and provide key mechanistic insights to genetic and pharmacological modulation of Aβ generation.
Insights
This study reveals intermediate steps in amyloid precursor protein (APP) processing by γ-secretase, clarifying Alzheimer's disease (AD) mechanisms. Familial AD mutations and γ-secretase modulators (GSMs) alter amyloid-beta (Aβ) peptide production pathways.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Amyloid precursor protein (APP) processing by γ-secretase generates amyloid-beta (Aβ) peptides.
- Accumulation of Aβ, particularly Aβ42, is linked to familial Alzheimer's disease (FAD).
- The precise mechanisms of normal Aβ production, FAD mutation impact, and γ-secretase modulator (GSM) effects remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of Aβ production.
- To investigate the impact of FAD mutations on Aβ generation.
- To understand how GSMs selectively reduce Aβ40 and Aβ42 levels.
Main Methods:
- Utilized a combined immuno- and liquid chromatography-mass spectrometry (LC-MS) assay.
- Identified major intermediate peptides (3- and 4-residue fragments) across the APP transmembrane sequence.
- Analyzed Aβ production in the context of FAD mutations and GSM treatment.
Main Results:
- Identified key intermediate peptides (e.g., Aβ51-30, Aβ49-30) in APP processing.
- FAD mutations increased specific intermediate peptides (Aβ48-38), correlating with higher Aβ42/40 ratios.
- GSMs decreased Aβ40/42 and increased shorter peptides (Aβ37/38) and specific intermediates (Aβ40-38, Aβ42-39).
Conclusions:
- Provided a comprehensive characterization of Aβ production intermediates in native cell membranes.
- Offered mechanistic insights into genetic and pharmacological modulation of Aβ generation.
- Established a foundation for understanding and targeting Alzheimer's disease pathogenesis.
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