The influence of Kallikrein-8 on Alzheimer disease-related neuroplasticity defects and tauopathy

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We previously identified Kallikrein-8 (KLK8) as a potential key player in the pathogenesis of Alzheimer disease (AD). We could detect excessive KLK8 mRNA and protein levels at incipient stages of AD, in both AD-affected and scarcely-affected brain areas of AD patients and transgenic (Tg) CRND8 mice. Moreover, we could show that short-term inhibition of cerebral KLK8 (for only four weeks) by an anti-KLK8 antibody at a moderate disease stage was sufficient to mitigate multiple features of Alzheimer pathology in Tg mice. Independent studies have shown that KLK8 modulates structural and electrochemical neuroplasticity by substrate turnover (processing of EPHB2, L1-CAM, neuregulin-1, fibronectin), modulation of synaptic tagging processes or by complex formation with binding partners such as PEBP-1. All of the aforementioned KLK8 interaction partners are also involved in AD. Work of our own lab has shown that KLK8 blockade in Tg brain increases expression of plasticity-controlling molecules, dendritic spine density and dendritic complexity, ultimately improving memory in Tg mice. The microtubule-associated protein tau, involved both in AD-related neurodegeneration and structural plasticity, is also connected to KLK8 signaling. Ligand-mediated activation of the KLK8 substrate EPHB2 inhibits tau hyper-phosphorylation, whereas the KLK8 down-stream target FKBP5 provokes tau oligomerization and accelerates neurotoxicity. Work in our own lab demonstrated that KLK8 inhibition protected EPHB2 from degradation and reduced tau pathology in Tg mice. With the present proposal we first aim to verify the therapeutic potential of KLK8 inhibition in AD. Therefore, we will genetically and permanently reduce KLK8 expression in Tg mice by crossbreeding with KLK8-knockdown mice, followed by behavioral phenotyping (spatial and recognition memory, agitation and anxiety) and quantification of amyloid beta pathology. Second, we will focus on the role of KLK8 in AD-related neuroplasticity disturbances. Accordingly, we will examine the in vivo and in vitro effects of short-term KLK8 inhibition, permanent KLK8 reduction or induction of KLK8 on neuronal proliferation, differentiation, and survival, dendritic complexity and spine density, as well as on KLK8 substrate turnover, synaptic tagging and complex-formation. Third, we will investigate the function of KLK8 in tau metabolism and therefore test the in vivo and in vitro effects of KLK8 inhibition, KLK8 reduction and KLK8 induction on physiologic and pathologic tau phosphorylation, intraneuronal tau distribution, and on tau-modulating EPHB2-dependent and EPHB2-independent signaling pathways. This project has the potential to verify KLK8 as a therapeutic target against AD and to gain new mechanistic insights in the interplay between KLK8, neuroplasticity and tau metabolism.