Ephrin B2 receptor signaling in Alzheimer diseased brain - a safeguard against neurodegeneration?

• Applicant: Privatdozent Dr. Arne Herring
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279728577

Ephrin B2 receptor (EPHB2) signaling, conducted by binding of Ephrin ligand EFNB2 to EPHB2, contributes to phenotypical brain plasticity at various levels. It coordinates angiogenesis and autophagy as well as memory and learning related axonal guidance / dendritic arborization and synapto/neurogenesis. Further, anxiety is controlled by kallikrein 8 (KLK8) mediated EPHB2 proteolysis and subsequent increased expression of FK506 binding protein 5 (FKBP5) which in turn regulates glucocorticoid receptor (GR) sensitivity in the amygdala. All the above named behavioral and structural processes that are controlled by EPHB2 are also disturbed / impaired in the Alzheimer disease (AD) affected brain. Therefore, it is very suggestive that EPHB2 signaling might be also involved in the pathogenesis of AD. The overall objective of this proposal is to elucidate the impact of EPHB2 signaling on the pathogenesis of AD. In particular, we aim to verify whether reversing EPHB2 depletion by inhibiting its proteolytic enzyme KLK8 would mitigate AD pathology, and if so to unravel the underlying mechanisms of this effect. First, in a descriptive approach, we aim to assess the regional and temporal specific mRNA and protein expression pattern of EPHB2 signaling members (EPHB2, EFNB2, KLK8, FKBP5, GR) in AD-vulnerable human and murine brain during the course of the disease (and physiological aging). Second, using an in vitro approach, we will mechanistically analyze the effect of pharmacological manipulation of EPHB2 signaling by a KLK8-inhibiting antibody (that protects EPHB2 from degradation) on Abeta pathology, autophagy and cell survival in primary neuronal and glial cell cultures derived from Tg mice. In a reciprocal approach, by using activated synthetic KLK8 we will then reduce EPHB2 levels and verify the above results inversely. Third, by using an in vivo approach, we will study the functional consequence of reversing EPHB2 signaling disturbance through intraventricular anti-KLK8 antibody administration to Tg mice (and to Wt mice serving as physiological baseline) on anxiety behavior as well as on learning and memory performances. Furthermore, the effect of this pharmacological manipulation on amygdalar molecules involved in anxiety generation and on hippocampal and cortical structural neuro-plasticity will be studied. Moreover, by performing molecular, structural and ultra-structural analyzes the impact of EPHB2 protection on APP and Abeta metabolism, Abeta clearance, the neurovascular unit and on autophagy machinery will be examined. Results from this project may open up new avenues in the treatment of AD.

• DFG Programme: Research Grants