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<p>The aim of this study is to assess the levels of meprin-β, an alternative β-secretase in the brain and cerebrospinal fluid of subjects suffering Alzheimer’s disease. The full-length zymogen and the active species of meprin-β were characterized by immunoblotting and immunoprecipitation using ectodomain N-terminal and C-terminal antibodies. We examined meprin-β changes in extracts from Alzheimer’s frontal cortex (<i>n</i> = 13, Braak stages I–II; <i>n</i> = 12, Braak stages III–IV; <i>n</i> = 12, Braak stages V-VI) compared with controls (<i>n</i> = 14), as well as in cerebrospinal fluid samples from Alzheimer’s patients (<i>n</i> = 15) or non-Alzheimer’s controls (<i>n</i> = 15). Cerebrospinal fluid meprin-β levels were also determined in 19-month old TgF344-AD and wild-type rats. Brain and cerebrospinal fluid from a <i>Mep1b</i>-null mouse served to characterize the specificity of the immunoreactive bands for meprin-β. Human induced pluripotent stem cell (iPSC)-derived neuronal cultures were treated with 2&#xa0;μM Aβ42 for 24&#xa0;h. We found that meprin-β is present in human brain extracts and cerebrospinal fluid as several distinct species, attributed to the zymogen and the mature species. These species were absent in brain and cerebrospinal fluid from a <i>Mep1b</i>-null mouse. No fragments of meprin-β were detected in brain extract, either in cerebrospinal fluid. Only the mature forms of meprin-β are increased in frontal cortex extracts (from Braak V-VI), but not the zymogen. The <i>MEP1-B</i> mRNA levels are increased in Braaks III-IV and V-VI compared with controls. The meprin-β species are increased in human neuronal cultures treated with Aβ42. Finally, we demonstrated elevated levels of the mature meprin-β in the cerebrospinal fluid of patients with Alzheimer’s disease and in TgF344-AD rats. Our data support a role of meprin-β in Alzheimer’s pathology.</p>

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Meprin-β levels are increased in the brain and the cerebrospinal fluid of Alzheimer’s disease patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Sergio Escamilla,
  • Carlos Avilés-Granados,
  • Carmen Márquez-Marco,
  • Maximilian Keller,
  • Irene Sánchez-Domínguez,
  • Inmaculada Cuchillo-Ibáñez,
  • Fernando Aguado,
  • Henrik Zetterberg,
  • Claus U. Pietrzik,
  • Javier Sáez-Valero

摘要

The aim of this study is to assess the levels of meprin-β, an alternative β-secretase in the brain and cerebrospinal fluid of subjects suffering Alzheimer’s disease. The full-length zymogen and the active species of meprin-β were characterized by immunoblotting and immunoprecipitation using ectodomain N-terminal and C-terminal antibodies. We examined meprin-β changes in extracts from Alzheimer’s frontal cortex (n = 13, Braak stages I–II; n = 12, Braak stages III–IV; n = 12, Braak stages V-VI) compared with controls (n = 14), as well as in cerebrospinal fluid samples from Alzheimer’s patients (n = 15) or non-Alzheimer’s controls (n = 15). Cerebrospinal fluid meprin-β levels were also determined in 19-month old TgF344-AD and wild-type rats. Brain and cerebrospinal fluid from a Mep1b-null mouse served to characterize the specificity of the immunoreactive bands for meprin-β. Human induced pluripotent stem cell (iPSC)-derived neuronal cultures were treated with 2 μM Aβ42 for 24 h. We found that meprin-β is present in human brain extracts and cerebrospinal fluid as several distinct species, attributed to the zymogen and the mature species. These species were absent in brain and cerebrospinal fluid from a Mep1b-null mouse. No fragments of meprin-β were detected in brain extract, either in cerebrospinal fluid. Only the mature forms of meprin-β are increased in frontal cortex extracts (from Braak V-VI), but not the zymogen. The MEP1-B mRNA levels are increased in Braaks III-IV and V-VI compared with controls. The meprin-β species are increased in human neuronal cultures treated with Aβ42. Finally, we demonstrated elevated levels of the mature meprin-β in the cerebrospinal fluid of patients with Alzheimer’s disease and in TgF344-AD rats. Our data support a role of meprin-β in Alzheimer’s pathology.