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<p>The dysregulation of proteostasis is a hallmark of Alzheimer’s disease (AD), characterized by the accumulation of misfolded and aggregated proteins. Dysfunction of the ubiquitin-proteasome pathway is a major contributing factor to proteostasis imbalance. The E3 ubiquitin ligase, F-box and WD repeat domain-containing 7 (FBXW7), a key hub factor in AD, is significantly downregulated in AD patients. FBXW7 mediates the proteasomal degradation of tau and regulates the development of tau pathology. However, the effect of FBXW7 on β-amyloid pathology and the underlying mechanisms remain unclear. This study demonstrated that FBXW7α, the dominant FBXW7 isoform, was localized in both the cytoplasm and nucleus of neurons. Aging led to a decline in FBXW7α protein levels in the brain tissues of both wild-type and 5×FAD mice. Notably, the level of FBXW7 in the brain tissue of 5×FAD mice is significantly lower than that in wild-type mice after 6 months of age. FBXW7α interacted with BACE1 via the conserved phosphodegron motif and targeted BACE1 for degradation. FBXW7 knockdown diminished the ubiquitination of BACE1, impaired its proteasome-mediated degradation, and increased the accumulation of BACE1 in Golgi fractions. Additionally, restoration of FBXW7α in the hippocampus improved cognitive function and ameliorated amyloid pathology in 5×FAD mice. Our findings suggest that FBXW7α acts as a key regulator of amyloid pathology, and highlight FBXW7α as a promising potential therapeutic target for AD intervention.</p><p></p>

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FBXW7α regulates amyloid pathology by mediating ubiquitination and degradation of BACE1 in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Yu Yang,
  • Luping Jia,
  • Jiachen Xu,
  • Jiwen Wu,
  • Haoyang Huang,
  • Hewen Yang,
  • Zihan Qi,
  • Yixuan Wang,
  • Hao Yu,
  • Shuai Wang

摘要

The dysregulation of proteostasis is a hallmark of Alzheimer’s disease (AD), characterized by the accumulation of misfolded and aggregated proteins. Dysfunction of the ubiquitin-proteasome pathway is a major contributing factor to proteostasis imbalance. The E3 ubiquitin ligase, F-box and WD repeat domain-containing 7 (FBXW7), a key hub factor in AD, is significantly downregulated in AD patients. FBXW7 mediates the proteasomal degradation of tau and regulates the development of tau pathology. However, the effect of FBXW7 on β-amyloid pathology and the underlying mechanisms remain unclear. This study demonstrated that FBXW7α, the dominant FBXW7 isoform, was localized in both the cytoplasm and nucleus of neurons. Aging led to a decline in FBXW7α protein levels in the brain tissues of both wild-type and 5×FAD mice. Notably, the level of FBXW7 in the brain tissue of 5×FAD mice is significantly lower than that in wild-type mice after 6 months of age. FBXW7α interacted with BACE1 via the conserved phosphodegron motif and targeted BACE1 for degradation. FBXW7 knockdown diminished the ubiquitination of BACE1, impaired its proteasome-mediated degradation, and increased the accumulation of BACE1 in Golgi fractions. Additionally, restoration of FBXW7α in the hippocampus improved cognitive function and ameliorated amyloid pathology in 5×FAD mice. Our findings suggest that FBXW7α acts as a key regulator of amyloid pathology, and highlight FBXW7α as a promising potential therapeutic target for AD intervention.