Inhibition of excessive kallikrein-8 improves neuroplasticity in Alzheimer's disease mouse model
| Autor: | Kathy Keyvani, Arne Herring, Yvonne Münster |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Neurite Receptor EphB2 Medizin Mice Transgenic tau Proteins 03 medical and health sciences Mice 0302 clinical medicine Developmental Neuroscience Alzheimer Disease Neuroplasticity Neurites Animals Humans Phosphorylation education Receptor Antibodies Blocking Cell Proliferation Injections Intraventricular Spatial Memory Neurons education.field_of_study Neuronal Plasticity biology Chemistry Neurogenesis Erythropoietin-producing hepatocellular (Eph) receptor Cell Differentiation Doublecortin Cell biology Mice Inbred C57BL 030104 developmental biology Phosphatidylethanolamine binding protein 1 Neurology biology.protein Kallikreins 030217 neurology & neurosurgery |
| Popis: | We recently identified excessive cerebral kallikrein-8 (KLK8) mRNA and protein levels at incipient stages of Alzheimer's disease (AD) in AD patients and TgCRND8 mice. Additionally, we showed that antibody-mediated KLK8 inhibition exerts therapeutic effects on AD along with enhancing neuroplasticity, resulting in improved spatial memory in mice. Mounting evidence further substantiates an important role of the protease KLK8 in neuroplasticity. In the present study we sought to gain new mechanistic insights in the interplay between KLK8, neuroplasticity and tau phosphorylation in the context of AD. We here demonstrate that KLK8 inhibition increased the number of hippocampal Ki-67 and doublecortin positive, proliferative neuronal progenitor cells in transgenic mice, whereas the same action in wildtypes had no effect. In line with these results, KLK8 inhibition reduced the levels of its pro-proliferative interaction partners KLK6 and protease-activated receptor 2 only in wildtypes, while the levels of its proliferation-supporting substrate neuregulin-1 and the non-complexed form of its complexing-partner phosphatidylethanolamine binding protein 1 were enhanced in both genotypes. Concomitant incubation of beta-amyloid (Aβ)-producing primary neurons with KLK8 and its inhibitory antibody increased neurite complexity and soma size. KLK8 inhibition in SH-SY5Y cells or in primary neurons increased levels of the neuroplasticity-supporting KLK8 substrate ephrin receptor B2 (EPHB2) and total tau while decreasing the relative amount of phospho-tau in relation to total tau. KLK8 blockade further enhanced cell proliferation in SH-SY5Y cells. Additional co-incubation with an inhibitory anti-EPHB2 antibody decreased total tau levels and neurite complexity and increased the ratio of phospho-tau/total tau, underlining the key role of EPHB2 on this plastic change. In a reverse in vitro approach, KLK8 induction reduced EPHB2 and total tau and increased the ratio of phospho-tau/total tau, leading to impaired proliferation and neuronal differentiation. These results underline the therapeutic potential of KLK8 inhibition by counteracting plasticity deficits in AD-affected brain. |
| Databáze: | OpenAIRE |
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