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Background <p>Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disorder with no effective cure, posing a major clinical challenge. Lysine 2-hydroxyisobutyrylation (Khib) is a recently identified post-translational modification found across diverse species and is involved in key metabolic processes associated with the regulation of protein function. However, its role in AD remains poorly understood. This study aimed to elucidate the involvement of Khib in AD pathogenesis as well as the underlying molecular mechanisms.</p> Methods <p>We compared lysine acylation profiles between 10-month-old APP/PS1 transgenic mice and age-matched wild-type (WT) controls using western blot. Quantitative Khib proteomics was employed to identify differentially modified proteins and specific Khib sites relevant to AD. To examine functional effects, we introduced an adeno-associated virus (AAV) vector expressing clusterin (CLU) K436R—a mutation that mimics Khib deficiency—into the bilateral lateral ventricles of 8-month-old WT and APP/PS1 mice via stereotactic injection. Additionally, C8-D1A astrocytic cells were transduced with lentivirus expressing CLU K436R. Co-immunoprecipitation was used to analyze the interaction between CLU and Aβ.</p> Results <p>Khib levels were significantly elevated in the brains of 10-month-old APP/PS1 mice. Proteomic analysis identified CLU as a Khib-modified protein, with K436 as the primary modification site. CLU K436 Khib levels were significantly upregulated in APP/PS1 mice. Notably, the loss of Khib at this site in CLU K436R mutant APP/PS1 mice led to marked suppressions in the number of β-amyloid plaques, gliosis, and neuroinflammation, along with improved memory performance in vivo. In vitro, CLU K436R expression in C8-D1A astrocytes promoted glial activation and cell viability. Mechanistically, the K436R mutation influenced the CLU–Aβ interaction, thereby modulating Aβ metabolism.</p> Conclusions <p>Our findings underscore a critical role for Khib in AD pathophysiology and reveal that Khib modification of CLU at K436 influences amyloid pathology, glial responses, and neuroinflammation. These results provide novel insights into the molecular mechanisms underlying AD and suggest that targeting Khib at CLU K436 may represent a promising therapeutic strategy.</p>

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De-2-hydroxyisobutyrylation of clusterin modulates neuropathology and memory deficits in an Alzheimer’s disease mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Xiaoping Peng,
  • Chaoyue Ouyang,
  • Fubin Ma,
  • Yu Liu,
  • Lv Luo,
  • Jiawei Xing,
  • Sifan Feng,
  • Li Li,
  • Jiahao Zhang,
  • Jiaying Wang,
  • Helei Cheng,
  • Tianying Zhang,
  • Feng Chen,
  • Yan Wang,
  • Lili Cui

摘要

Background

Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disorder with no effective cure, posing a major clinical challenge. Lysine 2-hydroxyisobutyrylation (Khib) is a recently identified post-translational modification found across diverse species and is involved in key metabolic processes associated with the regulation of protein function. However, its role in AD remains poorly understood. This study aimed to elucidate the involvement of Khib in AD pathogenesis as well as the underlying molecular mechanisms.

Methods

We compared lysine acylation profiles between 10-month-old APP/PS1 transgenic mice and age-matched wild-type (WT) controls using western blot. Quantitative Khib proteomics was employed to identify differentially modified proteins and specific Khib sites relevant to AD. To examine functional effects, we introduced an adeno-associated virus (AAV) vector expressing clusterin (CLU) K436R—a mutation that mimics Khib deficiency—into the bilateral lateral ventricles of 8-month-old WT and APP/PS1 mice via stereotactic injection. Additionally, C8-D1A astrocytic cells were transduced with lentivirus expressing CLU K436R. Co-immunoprecipitation was used to analyze the interaction between CLU and Aβ.

Results

Khib levels were significantly elevated in the brains of 10-month-old APP/PS1 mice. Proteomic analysis identified CLU as a Khib-modified protein, with K436 as the primary modification site. CLU K436 Khib levels were significantly upregulated in APP/PS1 mice. Notably, the loss of Khib at this site in CLU K436R mutant APP/PS1 mice led to marked suppressions in the number of β-amyloid plaques, gliosis, and neuroinflammation, along with improved memory performance in vivo. In vitro, CLU K436R expression in C8-D1A astrocytes promoted glial activation and cell viability. Mechanistically, the K436R mutation influenced the CLU–Aβ interaction, thereby modulating Aβ metabolism.

Conclusions

Our findings underscore a critical role for Khib in AD pathophysiology and reveal that Khib modification of CLU at K436 influences amyloid pathology, glial responses, and neuroinflammation. These results provide novel insights into the molecular mechanisms underlying AD and suggest that targeting Khib at CLU K436 may represent a promising therapeutic strategy.