Artikel
KLK8 inhibition attenuates Alzheimer’s pathology in mice
Suche in Medline nach
Autoren
Veröffentlicht: | 14. September 2016 |
---|
Gliederung
Text
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.