Kallikrein-8 inhibition attenuates Alzheimer’s pathology in mice

Herring, Arne; Münster, Yvonne; Akkaya, Tamer; Moghaddam, Sahar; Deinsberger, Katharina; Meyer, Jakob; Zahel, Julia; Sanchez-Mendoza, Eduardo; Wang, Yachao; Hermann, Dirk M. LSF; Arzberger, Thomas; Teuber-Hanselmann, Sarah; Keyvani, Kathy LSF

Introduction</br> </br> 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.</br> </br> Methods</br> </br> 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. </br> </br> Results</br> </br> 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, rAβ load and tau pathology, enhanced neuroplasticity, reversed molecular signatures of anxiety, and ultimately improved memory and reduced fear.</br> </br> Discussion</br> </br> Kallikrein-8 is a promising new therapeutic target against AD.

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Herring, A., Münster, Y., Akkaya, T., Moghaddam, S., Deinsberger, K., Meyer, J., Zahel, J., Sanchez-Mendoza, E., Wang, Y., Hermann, D.M., Arzberger, T., Teuber-Hanselmann, S., Keyvani, K., 2016. Kallikrein-8 inhibition attenuates Alzheimer’s pathology in mice. https://doi.org/10.1016/j.jalz.2016.05.006
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