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Alzheimers Dement. 2016 Dec;12(12):1273-1287. doi: 10.1016/j.jalz.2016.05.006. Epub 2016 Jun 18.

Kallikrein-8 inhibition attenuates Alzheimer's disease pathology in mice.

Author information

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.

KEYWORDS:

Alzheimer's disease; Anxiety; Autophagy; Aβ clearance; Aβ pathology; Ephrin receptor B2; Intraventricular antibody delivery; Kallikrein-8; Neuroplasticity; tau pathology

PMID:
27327541
DOI:
10.1016/j.jalz.2016.05.006
[Indexed for MEDLINE]
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