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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Heng Liu,
  • Firoz Akhter,
  • Asma Akhter,
  • Xue Zhao,
  • Xudong Wang,
  • Haiqiang Yang,
  • Jianyu Chen,
  • Xinyu Xia,
  • Laurent Calcul,
  • Yi He,
  • Chuanhai Cao,
  • Libin Ye,
  • Donghui Zhu,
  • Jianfeng Cai

摘要

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.