Arne Herring1, Yvonne Münster2, Tamer Akkaya2, Sahar Moghaddam2, Katharina Deinsberger2, Jakob Meyer2, Julia Zahel2, Eduardo Sanchez-Mendoza3, Yachao Wang3, Dirk M Hermann3, Thomas Arzberger4, Sarah Teuber-Hanselmann2, Kathy Keyvani5. 1. Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. Electronic address: arne.herring@uk-essen.de. 2. Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. 3. Department of Neurology, University of Duisburg-Essen, Essen, Germany. 4. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany; Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany. 5. Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. Electronic address: kathy.keyvani@uk-essen.de.
Abstract
INTRODUCTION: Memory loss and increased anxiety are clinical hallmarks of Alzheimer's disease (AD). Kallikrein-8 is a protease implicated in memory acquisition and anxiety, and its mRNA is known to be up-regulated in AD-affected human hippocampus. Therefore, an involvement of Kallikrein-8 in Alzheimer's pathogenesis is conceivable but remains to be proved. METHODS: We determined the cerebral expression of Kallikrein-8 mRNA and protein during the course of AD in patients and in transgenic mice and tested the impact of Kallikrein-8 inhibition on AD-related pathology in mice and in primary glial cells. RESULTS: Kallikrein-8 mRNA and protein were up-regulated in both species at incipient stages of AD. Kallikrein-8 inhibition impeded amyloidogenic amyloid-precursor-protein processing, facilitated amyloid β (Aβ) clearance across the blood-brain-barrier, boosted autophagy, reduced Aβ load and tau pathology, enhanced neuroplasticity, reversed molecular signatures of anxiety, and ultimately improved memory and reduced fear. DISCUSSION: Kallikrein-8 is a promising new therapeutic target against AD.
INTRODUCTION:Memory loss and increased anxiety are clinical hallmarks of Alzheimer's disease (AD). Kallikrein-8 is a protease implicated in memory acquisition and anxiety, and its mRNA is known to be up-regulated in AD-affected human hippocampus. Therefore, an involvement of Kallikrein-8 in Alzheimer's pathogenesis is conceivable but remains to be proved. METHODS: We determined the cerebral expression of Kallikrein-8 mRNA and protein during the course of AD in patients and in transgenic mice and tested the impact of Kallikrein-8 inhibition on AD-related pathology in mice and in primary glial cells. RESULTS:Kallikrein-8 mRNA and protein were up-regulated in both species at incipient stages of AD. Kallikrein-8 inhibition impeded amyloidogenic amyloid-precursor-protein processing, facilitated amyloid β (Aβ) clearance across the blood-brain-barrier, boosted autophagy, reduced Aβ load and tau pathology, enhanced neuroplasticity, reversed molecular signatures of anxiety, and ultimately improved memory and reduced fear. DISCUSSION: Kallikrein-8 is a promising new therapeutic target against AD.
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