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Updated: May 13, 2026

A11-positive β-amyloid Oligomer Preparation and Assessment Using Dot Blotting Analysis
Published on: May 22, 2018
α/Sulfonyl-γ-AApeptide foldamers mitigate Alzheimer's disease pathology by stabilizing transient helical domains in
Heng Liu1, Firoz Akhter2, Asma Akhter2
1Department of Chemistry, University of South Florida, Tampa, FL, USA.
Abstract:
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ), with soluble oligomers widely recognized as key drivers of neurotoxicity through disruption of synaptic function, mitochondrial integrity, and cellular homeostasis. Targeting Aβ aggregation therefore represents a compelling therapeutic strategy. Here we report a synthetic peptidomimetic foldamer, M4, as a potent modulator of Aβ42 aggregation. Biophysical analyses demonstrate that M4 binds Aβ with high affinity, inhibits oligomer formation, and remodels pre-existing aggregates, likely by stabilizing a helical conformation that disfavors β-sheet assembly. In primary neurons, M4 restores synaptic protein levels, reduces oxidative stress, and preserves mitochondrial membrane potential. In a 5xFAD mouse model, M4 attenuates neuroinflammation, reduces Aβ burden, and improves cognitive performance. Pharmacokinetic studies further reveal favorable brain penetration and metabolic stability. Collectively, these findings establish M4 as a promising candidate for targeting Aβ-mediated pathology in AD.
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