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



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.



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.



Kallikrein-8 is a promising new therapeutic target against AD.
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. Electronic address: arne.herring@uk-essen.de.
Arne
A
Herring
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Yvonne
Y
Münster
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Tamer
T
Akkaya
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Sahar
S
Moghaddam
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Katharina
K
Deinsberger
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Jakob
J
Meyer
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Julia
J
Zahel
Department of Neurology, University of Duisburg-Essen, Essen, Germany.
Eduardo
E
Sanchez-Mendoza
Department of Neurology, University of Duisburg-Essen, Essen, Germany.
Yachao
Y
Wang
Department of Neurology, University of Duisburg-Essen, Essen, Germany.
Dirk M
DM
Hermann
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany; Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Thomas
T
Arzberger
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
Sarah
S
Teuber-Hanselmann
Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. Electronic address: kathy.keyvani@uk-essen.de.
Kathy
K
Keyvani
D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus; D006801:Humans; D007610:Kallikreins; D051379:Mice; D008822:Mice, Transgenic
D016564:Amyloid beta-Protein Precursor; D007610:Kallikreins
Alzheimer's disease; Anxiety; Autophagy; Aβ clearance; Aβ pathology; Ephrin receptor B2; Intraventricular antibody delivery; Kallikrein-8; Neuroplasticity; tau pathology