Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-β-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity
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Diverse lines of evidence suggest that amyloid- (A) peptides causally contribute to the pathogenesis of Alzheimer disease (AD), the most frequent neurodegenerative disorder.However, the mechanisms by which A impairs neuronal functions remain to be fully elucidated.Previous studies showed that soluble A oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process.Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wild-type or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity but not on its kinase activity.We further present evidence that the protective effect of EphB2 may be mediated by the AMPA-type glutamate receptor subunit GluA2, which can become associated with the PDZ-binding motif of EphB2 through PDZ domain-containing proteins and can promote the retention of NMDARs in the membrane.In addition, we show that the A-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of A-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrP C ), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the A-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity-and PDZ-dependent regulation of AMPA-type glutamate receptors.Alzheimer disease (AD) 3 is the most common neurodegenerative disorder, affecting millions of elderly people worldwide (1).Disease-modifying treatments are urgently needed because the number of AD patients is rising as many populations across the world live longer, reaching ages at which the risk of AD is high.It is likely that the development of such treatments will require a deeper understanding of AD pathogenesis, which appears to be multifactorial (2).Diverse lines of evidence suggest that amyloid- (A) oligomers causally contribute to cognitive impairments associated with AD at least partly by altering synaptic activity (2-6).Synaptic activity and cognition critically depend on the function of NMDA-type glutamate receptors (NMDARs) and AMPA-type glutamate receptors (AMPARs), both of which appear to be affected by A oligomers.Indeed, A oligomers deplete and dysregulate NMDARs (7-12) and AMPARs (9, 13, 14).However, the precise molecular paths that lead from A oligomers to alterations in these glutamate receptors remain to be elucidated.Several factors, including tau, aberrant network activity, and prion protein (PrP C ), may mediate or enable A-induced neuronal dysfunctions.We and others showed that tau reduction prevents synaptic, network, and behavioral abnormalities in multiple human amyloid precursor protein (hAPP) transgenic mouse lines that have pathologically elevated levels of A oligomers in brain (15)(16)(17)(18).Several studies suggest that aberrant excitatory network activity, which tau reduction can block (15-17), contributes to synaptic and cognitive deficits in hAPP mice and in patients with early stages of AD (19 -23).PrP C has also been reported to be required for A-induced neuronal and cognitive impairments and has been proposed to mediate A-induced depletion of NMDARs (24 -27), although several of these findings could not be reproduced by other groups (28 -30).Another interesting molecule that may connect A oligomers to glutamate receptors is the receptor tyrosine kinase EphB2 (12,31,32), which regulates the trafficking and function of NMDARs (33).A oligomers directly bind to EphB2 (32) and * This work was supported in part by National Institutes of Health Grant NS041787 (to L. M.).The authors declare that they have no conflicts of interest with the contents of this article.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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EphB2 overexpression can restore reductions in AMPAR and NMDAR levels induced by oAβ.
“In addition, EphB2 overexpression can restore reductions in AMPAR and NMDAR levels induced by oAβ.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [77]
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- Authors
- Miyamoto, T., Kim, D., Knox, J. A., Johnson, E., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Mucke, Lennart
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 291
- Issue
- 4
- Pages
- 1719-1734
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4722453
- OpenAlex
- W2174648861
- Cited by
- 33
- References
- 75
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 1 · 2018: 8 · 2017: 3 · 2016: 3
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (NS041787)
- Japan Society for the Promotion of Science (Postdoctoral Fellowship for Research Abroad)
- Uehara Memorial Foundation (Research Fellowship)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- EphB2, amyloid-beta, Alzheimer's disease, AMPA receptors, GluA2, PDZ-binding motif, PDZ domain, neuronal activity, receptor tyrosine kinase, synaptic dysfunction, soluble amyloid-beta oligomers, disease-modifying therapy, tau protein, prion protein, kinase-independent signaling
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Female, Hippocampus, Humans, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Protein Binding, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Receptors, AMPA, Mice, Knockout, Amino Acid Motifs, Receptor, EphB2, Mice, PDZ Domains
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