Lipocalin-type prostaglandin D synthase/β-trace is a major amyloid β-chaperone in human cerebrospinal fluid

Takahisa Kanekiyo, Tadato Ban, Kosuke Aritake, Zhi Li Huang, Wei Min Qu, Issay Okazaki, Ikuko Mohri, Shigeo Murayama, Keiichi Ozono, Masako Taniike, Yuji Goto, Yoshihiro Urade

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100 Scopus citations

Abstract

The conformational change in amyloid β (Aβ) peptide from its monomeric form to aggregates is crucial in the pathogenesis of Alzheimer's disease (AD). In the healthy brain, some unidentified chaperones appear to prevent the aggregation of Aβ. Here we reported that lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace, the most abundant cerebrospinal fluid (CSF) protein produced in the brain, was localized in amyloid plaques in both AD patients and AD-model Tg2576 mice. Surface plasmon resonance analysis revealed that L-PGDS/β-trace tightly bound to Aβ monomers and fibrils with high affinity (KD = 18-50 nM) and that L-PGDS/β-trace recognized residues 25-28 in Aβ, which is the key region for its conformational change to a β-sheet structure. The results of a thioflavin T fluorescence assay to monitor Aβ aggregation disclosed that L-PGDS/β-trace inhibited the spontaneous aggregation of Aβ (1-40) and Aβ (1-42) within its physiological range (1-5 μM) in CSF. L-PGDS/β-trace also prevented the seed-dependent aggregation of 50 μM Aβ with Ki of 0.75 μM. Moreover, the inhibitory activity toward Aβ (1-40) aggregation in human CSF was decreased by 60% when L-PGDS/β-trace was removed from the CSF by immunoaffinity chromatography. The deposition of Aβ after intraventricular infusion of Aβ (1-42) was 3.5-fold higher in L-PGDS-deficient mice and reduced to 23% in L-PGDS-overexpressing mice as compared with their wild-type levels. These data indicate that L-PGDS/β-trace is a major endogenous Aβ-chaperone in the brain and suggest that the disturbance of this function may be involved in the onset and progression of AD. Our findings may provide a diagnostic and therapeutic approach for AD.

Original languageEnglish (US)
Pages (from-to)6412-6417
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number15
DOIs
StatePublished - Apr 10 2007

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Keywords

  • Aggregation
  • Alzheimer's disease
  • Mouse
  • Surface plasmon resonance
  • Thioflavin T

ASJC Scopus subject areas

  • General

Cite this

Kanekiyo, T., Ban, T., Aritake, K., Huang, Z. L., Qu, W. M., Okazaki, I., Mohri, I., Murayama, S., Ozono, K., Taniike, M., Goto, Y., & Urade, Y. (2007). Lipocalin-type prostaglandin D synthase/β-trace is a major amyloid β-chaperone in human cerebrospinal fluid. Proceedings of the National Academy of Sciences of the United States of America, 104(15), 6412-6417. https://doi.org/10.1073/pnas.0701585104