Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.

TitleReversing EphB2 depletion rescues cognitive functions in Alzheimer model.
Publication TypeJournal Article
Year of Publication2011
AuthorsCissé M, Halabisky B, Harris J, Devidze N, Dubal DB, Sun B, Orr A, Lotz G, Kim DH, Hamto P, Ho K, Yu G-Q, Mucke L
JournalNature
Volume469
Issue7328
Pagination47-52
Date Published2011 Jan 06
ISSN1476-4687
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Cell Line, Cells, Cultured, Cognition, Dentate Gyrus, Disease Models, Animal, Humans, Long-Term Potentiation, Memory, Mice, Mice, Transgenic, Neuronal Plasticity, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Tertiary, Rats, Receptor, EphB2, Receptors, N-Methyl-D-Aspartate, Synapses
Abstract

Amyloid-β oligomers may cause cognitive deficits in Alzheimer's disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer's disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer's disease.

DOI10.1038/nature09635
Alternate JournalNature
PubMed ID21113149
PubMed Central IDPMC3030448
Grant ListR01 AG011385 / AG / NIA NIH HHS / United States
NS041787 / NS / NINDS NIH HHS / United States
R01 NS041787 / NS / NINDS NIH HHS / United States
RR18928-01 / RR / NCRR NIH HHS / United States
R01 AG011385-08 / AG / NIA NIH HHS / United States
AG011385 / AG / NIA NIH HHS / United States
AG022074 / AG / NIA NIH HHS / United States
P01 AG022074 / AG / NIA NIH HHS / United States
R01 NS041787-09 / NS / NINDS NIH HHS / United States
P01 AG022074-09 / AG / NIA NIH HHS / United States
R37 AG011385 / AG / NIA NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States