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Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice
Author(s) -
Herring Arne,
Münster Yvonne,
Akkaya Tamer,
Moghaddam Sahar,
Deinsberger Katharina,
Meyer Jakob,
Zahel Julia,
SanchezMendoza Eduardo,
Wang Yachao,
Hermann Dirk M.,
Arzberger Thomas,
TeuberHanselmann Sarah,
Keyvani Kathy
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.05.006
Subject(s) - kallikrein , genetically modified mouse , senile plaques , autophagy , hippocampus , alzheimer's disease , pathogenesis , amyloid precursor protein , transgene , amyloid (mycology) , biology , neuroscience , medicine , pathology , disease , endocrinology , gene , biochemistry , apoptosis , enzyme
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.