Artikel
KLK8 inhibition attenuates Alzheimer’s pathology in mice
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Autoren
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Arne Herring
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Yvonne Münster
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Tamer Akkaya
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Sahar Moghaddam
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Katharina Deinsberger
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Jakob Meyer
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Julia Zahel
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Eduardo Sanchez-Mendoza
- University of Duisburg-Essen, Department of Neurology, Essen, Germany
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Yachao Wang
- University of Duisburg-Essen, Department of Neurology, Essen, Germany
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Dirk Hermann
- University of Duisburg-Essen, Department of Neurology, Essen, Germany
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Thomas Arzberger
- Ludwig-Maximilians-University Munich, Department of Psychiatry and Psychotherapy, Munich, Germany; Ludwig-Maximilians-University Munich, Center for Neuropathology and Prion Research, Munich, Germany
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Sarah Teuber Hanselmann
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
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Kathy Keyvani
- University of Duisburg-Essen, Institute of Neuropathology, Essen, Germany
| Veröffentlicht: | 14. September 2016 |
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Gliederung
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Introduction & Objectives: Memory loss and increased anxiety are clinical hallmarks of Alzheimer’s disease (AD). The serine protease kallikrein-8 (KLK8) is implicated in synaptic plasticity and memory acquisition as well as in anxiety-related behavior. KLK8 mRNA is further known to be up-regulated in AD-affected human hippocampus. Accordingly, we asked whether KLK8 might be involved in the pathogenesis of AD.
Patients & Methods: We determined the cerebral mRNA and protein expression pattern of KLK8 and its substrate Ephrin receptor B2 (EPHB2), as well as the downstream signaling members FK506 binding protein-5 and Ephrin ligand B2 during the course of disease progression in AD patients (classified as CERAD A/Braak I-II, CERAD B/Braak III-IV, CERAD C/Braak V-VI) and in transgenic CRND8 mice (prior to disease onset and in early until late disease stages). Using an anti-KLK8 antibody, we further tested the impact of KLK8 inhibition on AD related behavioral, structural and molecular dysfunctions in murine brain and in primary glial cell culture.
Results: Here, we demonstrate a drastic up-regulation of KLK8 mRNA and protein in human and murine brain at incipient stages of Alzheimer’s pathology, long before any behavioral signs of disease appear and prior to EPHB2 depletion. In transgenic mice KLK8 blockade intervened in amyloid β (Aβ) metabolism by impeding amyloidogenic amyloid precursor protein processing, facilitating Aβ clearance across the blood-brain-barrier and boosting the autophagy machinery, thereby reducing cerebral Aβ load. These effects were partially transduced by restoration of EPHB2, as in vitro blockade of EPHB2 abolished the positive effects of KLK8 inhibition on microglial amyloid clearance. Additionally, anti-KLK8 antibody administration diminished tau pathology as verum treated transgenic mice displayed reduced neuritic plaque burden and tau hyperphosphorylation, mediated by activation of the kinases PI3K and Akt and thus down-stream inhibition of the tau phosphorylating kinase GSK3β. Moreover, KLK8 inhibition enhanced structural plasticity and reversed the molecular signatures of anxiety, along with improving memory performance and reducing fear.
Conclusions: Our results identify KLK8 as a promising antecedent biomarker for and a new therapeutic target against AD.
