Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.
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.
Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
Moustapha
M
Cissé
Brian
B
Halabisky
Julie
J
Harris
Nino
N
Devidze
Dena B
DB
Dubal
Binggui
B
Sun
Anna
A
Orr
Gregor
G
Lotz
Daniel H
DH
Kim
Patricia
P
Hamto
Kaitlyn
K
Ho
Gui-Qiu
GQ
Yu
Lennart
L
Mucke
D000544:Alzheimer Disease / Q000503:physiopathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003071:Cognition / Q000502:physiology*; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D017774:Long-Term Potentiation; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D036183:Receptor, EphB2 / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D036183:Receptor, EphB2; D046988:Proteasome Endopeptidase Complex