The influence of Kallikrein-8 on Alzheimer disease-related neuroplasticity defects and tauopathy
Final Report Abstract
This project aimed to determine the influence of kallikrein-8 (KLK8) on Alzheimer’s disease (AD)-related neuroplasticity defects and tauopathy and to validate KLK8 as a potential therapeutic target. First, we tested whether KLK8 manipulation via inhibitory anti-KLK8 and anti-EPHB2 antibodies or KLK8 induction via treatment with recombinant KLK8 affect AD-related pathology in transgenic and wildtype control mice as well as in primary neurons and SH-SY5Y cell line. We could show that short-term inhibition of cerebral KLK8 improved various aspects of neuroplasticity such as cell proliferation and up-regulation of neuroplasticity-associated KLK8 substrates and interaction partners predominantly in hippocampus of transgenic animals. Confirmatory, KLK8 blockade promoted, whereas KLK8 induction hampered cell proliferation and neurite complexity without affecting cell survival in vitro. Moreover, KLK8 inhibition reversed KLK8-triggered tau reduction and its hyperphosphorylation in primary neurons and cell line. Simultaneous blockade of EPHB2 abolished the beneficial effects of KLK8 inhibition on neurite complexity and tau metabolism, indicating a decisive role of proper EPHB2 signal transduction in these plasticity processes. With a second project-related study we investigated sex-specific effects of permanent KLK8 reduction by genetic mKlk8 knockdown on AD-like pathology in mice and associated primary cells. We could demonstrate that mKlk8 knockdown was anxiolytic, increased exploration and improved memory in transgenics. Further, permanent KLK8 reduction promoted adult hippocampal neurogenesis and structural neuroplasticity, mitigated Aβ pathology and neurovascular dysfunction, and boosted cerebral autophagy and microglial fitness in transgenic mice in a sex-specific manner. In vitro, mKlk8 knockdown improved primary neuronal and glial survival, reduced neuronal Aβ production/secretion and enhanced microglial Aβ phagocytosis. Recent studies by us further suggest KLK8-mediated, excessive degradation of APOE4, the most prominent AD risk factor, failures in the KLK8 inhibition network and a role of KLK8 in kallikrein-kinin-system hyperactivity in AD. Together, these results indicate that KLK8 dysregulation propels AD pathogenesis by multiple proceedings and underscore KLK8 as a novel therapeutic target in AD.
Publications
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Inhibition of excessive kallikrein-8 improves neuroplasticity in Alzheimer's disease mouse model. Experimental Neurology, 324, 113115.
Münster, Yvonne; Keyvani, Kathy & Herring, Arne
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Agents inhibiting Kallikrein-8 for use in the prevention or treatment of Alzheimer's disease”; Patent No. 3353214, issued by the European Patent Agency on 22/07/2021
Arne Herring and Kathy Keyvani
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Genetic knockdown of Klk8 has sex‐specific multi‐targeted therapeutic effects on Alzheimer’s pathology in mice. Neuropathology and Applied Neurobiology, 47(5), 611-624.
Herring, Arne; Kurapati, Nirup K.; Krebs, Sofia; Grammon, Nils; Scholz, Luisa M.; Voss, Gerrit; Miah, Muhammad R.; Budny, Vanessa; Mairinger, Fabian; Haase, Katharina; Teuber‐Hanselmann, Sarah; Dobersalske, Celia; Schramm, Sara; Jöckel, Karl‐Heinz; Münster, Yvonne & Keyvani, Kathy
