Perspectives on Treatment of Alzheimer's Disease: A Closer Look into EphB2 Depletion

Dijken, Irene van; Vlag, Marc van der; Flores-Hernández, Raquel; Ross, Anne M.

doi:10.1523/jneurosci.0214-17.2017

Cited by 5 publications

(6 citation statements)

References 14 publications

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“…Together with the accumulating evidences, EphB2 mediates the excitatory synaptogenesis during development and coordinates synaptic plasticity by controlling the localization and function of glutamate receptors 27,59 . Previous studies also show that EphB2 signal is related to anxiety disorders 62 , autism 63,64 , and cognitive dysfunction 41,65 . Our study expands the understanding of the (see figure on previous page) Fig.…”

Section: Discussionmentioning

confidence: 79%

EphB2 mediates social isolation-induced memory forgetting

et al. 2020

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Social isolation in adolescence leads to lasting deficits, including emotional and cognitive dysregulation. It remains unclear, however, how social isolation affects certain processes of memory and what molecular mechanisms are involved. In this study, we found that social isolation during the post-weaning period resulted in forgetting of the long-term fear memory, which was attributable to the downregulation of synaptic function in the hippocampal CA1 region mediated by EphB2, a receptor tyrosine kinase which involves in the glutamate receptor multiprotein complex. Viral-mediated EphB2 knockdown in CA1 mimicked the memory defects in group-housed mice, whereas restoration of EphB2 by either viral overexpression or resocialization reversed the memory decline in isolated mice. Taken together, our finding indicates that social isolation gives rise to memory forgetting by disrupting EphB2-mediated synaptic plasticity, which may provide a potential target for preventing memory loss caused by social isolation or loneliness.

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Section: Discussionmentioning

confidence: 79%

EphB2 mediates social isolation-induced memory forgetting

et al. 2020

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“…We have focused our efforts on exploring whether GSMs affect the processing of E‐cadherin, ephrin type B receptor 2 (EphB2) and ephrin type A receptor 4 (EphA4), which are known to mediate important cell signalling and may have been associated with severe side effects in response to γ‐secretase inhibitor trials (i.e., semagacestat and avagacestat). 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 We find that GSMs, in contrast to their effect on APP processing, do not affect the processing of E‐cadherin, EphB2 and EphA4 to a large extent. Rather, our data suggest that GSMs are selective for γ‐secretase–mediated APP processing and support the further development of GSMs as a tolerable and effective anti‐amyloidogenic treatment for the treatment of AD.…”

Section: Introductionmentioning

confidence: 68%

“…A key objective of the current study was to study how GSM as a class of anti‐amyloid agents affects γ‐secretase–catalysed reactions in a broader context beyond APP and Notch processing. We chose to study EphB2, EphA4 and E‐cadherin processing based on their documented function and important signalling in different physiological and pathophysiological contexts, such as synaptic plasticity, memory formation, cell proliferation and cancer, 27 , 28 , 29 , 30 , 31 , 32 , 33 which have been implicated in the adverse events associated with γ‐secretase inhibitor trials in AD patients. 13 , 14 …”

Section: Discussionmentioning

confidence: 99%

“…In this study, we have taken advantage of the N‐terminal FLAG‐tagging strategy to extend our analysis of the pharmacology of GSM to less well‐characterized γ‐secretase–catalysed reactions. We have focused our efforts on exploring whether GSMs affect the processing of E‐cadherin, ephrin type B receptor 2 (EphB2) and ephrin type A receptor 4 (EphA4), which are known to mediate important cell signalling and may have been associated with severe side effects in response to γ‐secretase inhibitor trials (i.e., semagacestat and avagacestat) 27–34 …”

Section: Introductionmentioning

confidence: 99%

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γ‐Secretase modulators show selectivity for γ‐secretase–mediated amyloid precursor protein intramembrane processing

Weber

Lundkvist

Wanngren

et al. 2021

J Cellular Molecular Medi

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The aggregation of β‐amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ‐secretase–mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ‐Secretase modulators (GSMs) represent a promising class of Aβ42‐lowering anti‐amyloidogenic compounds for the treatment of AD. Gamma‐secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ‐secretase–mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ‐secretase cleavage of three γ‐secretase substrates, E‐cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ‐secretase–dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ‐secretase processing of EphA4 and EphB2 results in the release of several Aβ‐like peptides, but that only the production of Aβ‐like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ‐secretase–mediated Aβ production.

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“…Moreover, it has been shown that Alzheimer disease-linked amyloid-β oligomers bind to the fibronectin domains of EphB2 and trigger receptor degradation in the proteasome [ 14 ]. Thus, augmenting EphB2 activity could have beneficial effects in Alzheimer disease by reversing long-term potentiation impairments [ 15 ]. Therapeutic strategies targeting amyloid-β oligomers were recently reviewed in [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism

Robev

Saha

et al. 2021

IJMS

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The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph–Eph interfaces. One Eph–Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor–receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.

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Perspectives on Treatment of Alzheimer's Disease: A Closer Look into EphB2 Depletion

Cited by 5 publications

References 14 publications

EphB2 mediates social isolation-induced memory forgetting

EphB2 mediates social isolation-induced memory forgetting

γ‐Secretase modulators show selectivity for γ‐secretase–mediated amyloid precursor protein intramembrane processing

The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism

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