α/Sulfonyl-γ-AApeptide foldamers mitigate Alzheimer's disease pathology by stabilizing transient helical domains in Aβ.

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.