Attenuated Abeta42 responses to low potency gamma-secretase modulators can be overcome for many pathogenic presenilin
Benedikt Kretner1, Akio Fukumori, Amelie Gutsmiedl
1DZNE-German Center for Neurodegenerative Diseases, Ludwig-Maximilians-University, 80336 Munich, Germany.
Abstract:
Sequential processing of the β-amyloid precursor protein by β- and γ-secretase generates the amyloid β-peptide (Aβ), which is widely believed to play a causative role in Alzheimer disease. Selective lowering of the pathogenic 42-amino acid variant of Aβ by γ-secretase modulators (GSMs) is a promising therapeutic strategy. Here we report that mutations in presenilin (PS), the catalytic subunit of γ-secretase, display differential responses to non-steroidal anti-inflammatory drug (NSAID)-type GSMs and more potent second-generation compounds. Although many pathogenic PS mutations resisted lowering of Aβ(42) generation by the NSAID sulindac sulfide, the potent NSAID-like second-generation compound GSM-1 was capable of lowering Aβ(42) for many but not all mutants. We further found that mutations at homologous positions in PS1 and PS2 can elicit differential Aβ(42) responses to GSM-1, suggesting that a positive GSM-1 response depends on the spatial environment in γ-secretase. The aggressive pathogenic PS1 L166P mutation was one of the few pathogenic mutations that resisted GSM-1, and Leu-166 was identified as a critical residue with respect to the Aβ(42)-lowering response of GSM-1. Finally, we found that GSM-1-responsive and -resistant PS mutants behave very similarly toward other potent second-generation compounds of different structural classes than GSM-1. Taken together, our data show that a positive Aβ(42) response for PS mutants depends both on the particular mutation and the GSM used and that attenuated Aβ(42) responses to low potency GSMs can be overcome for many PS mutants by second generation GSMs.
Insights
Certain mutations in presenilin (PS) impact how effectively γ-secretase modulators (GSMs) lower amyloid β-peptide (Aβ) levels. Potent second-generation GSMs can overcome resistance seen with older compounds, offering new therapeutic avenues for Alzheimer disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Drug Discovery
Background:
- Alzheimer disease pathogenesis is linked to amyloid β-peptide (Aβ) production via β- and γ-secretase.
- Selective reduction of pathogenic Aβ variants using γ-secretase modulators (GSMs) is a key therapeutic strategy.
- Presenilin (PS) mutations, the catalytic core of γ-secretase, can influence Aβ production.
Purpose of the Study:
- To investigate the differential responses of presenilin (PS) mutations to various γ-secretase modulators (GSMs).
- To determine if potent second-generation GSMs can overcome resistance in PS mutants.
- To identify key residues and spatial factors influencing GSM efficacy.
Main Methods:
- Assessing the effect of NSAID-type and second-generation GSMs on Aβ(42) generation in cells expressing various PS mutations.
- Comparing responses of homologous PS1 and PS2 mutations to GSM-1.
- Identifying critical residues like Leu-166 in PS1 through mutation analysis.
Main Results:
- Many pathogenic PS mutations showed resistance to lowering Aβ(42) by NSAID-type GSMs.
- The potent GSM-1 effectively lowered Aβ(42) in many, but not all, PS mutants.
- Homologous PS1 and PS2 mutations exhibited differential responses to GSM-1, indicating dependence on the γ-secretase microenvironment.
- The PS1 L166P mutation was resistant to GSM-1, highlighting Leu-166's importance.
- PS mutants responded similarly to various potent second-generation GSMs, regardless of structural class.
Conclusions:
- The efficacy of GSMs in reducing Aβ(42) is dependent on both the specific PS mutation and the modulator used.
- Potent second-generation GSMs can restore therapeutic efficacy for many PS mutants resistant to lower-potency compounds.
- Understanding these differential responses is crucial for developing effective Alzheimer disease therapeutics targeting Aβ production.
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