Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice.
Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.
A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
Susanna
S
Kemppainen
Tomi
T
Rantamäki
André
A
Jerónimo-Santos
Gregoire
G
Lavasseur
Henri
H
Autio
Nina
N
Karpova
Elisa
E
Kärkkäinen
Saara
S
Stavén
Hugo
H
Vicente Miranda
Tiago F
TF
Outeiro
Maria J
MJ
Diógenes
Serge
S
Laroche
Sabrina
S
Davis
Ana M
AM
Sebastião
Eero
E
Castrén
Heikki
H
Tanila
D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000096:biosynthesis / Q000235:genetics*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D020813:Receptor, trkB