Involvement of insulin-like growth factor 1 receptor signaling in the amyloid-β peptide oligomers-induced p75 neurotrophin receptor protein expression in mouse hippocampus.
The p75 neurotrophin receptor (p75NTR) has been thought to play a critical role in amyloid-β peptide (Aβ)-mediated neurodegeneration and Aβ metabolism in Alzheimer's disease (AD) brains. Our previous report showed that membrane-associated p75NTR protein expression was significantly increased in the hippocampi of two different strains of transgenic AD mice and was associated with the age-dependent elevation of Aβ1-42 levels. Here, we provide evidence that the Aβ1-42 oligomers known as ADDLs (Aβ-derived diffusible ligands) induce p75NTR protein expression through insulin-like growth factor 1 receptor (IGF-1R) phosphorylation in SH-SY5Y human neuroblastoma cells. An in vivo microinjection study demonstrated that microinjected ADDLs increased the p75NTR protein expression by 1.4-fold in the ipsilateral hippocampus compared to the contralateral hippocampus. In addition, ADDLs microinjected into mouse hippocampi facilitated IGF-1R phosphorylation within 30 min and the co-administration of picropodophyllin, an IGF-1R kinase inhibitor, blocked ADDLs-induced p75NTR expression. We examined the possible involvement of IGF-1R in the increased p75NTR protein expression in the hippocampi of 6-month-old AβPPswe/PS1dE9 AD model mice that had accumulated significant amounts of Aβ1-42 and showed significantly higher p75NTR expression than age-matched wild-type mice. We found that IGF-1R phosphorylation in these transgenic mice was higher than that in the wild-type mice. These findings indicate that Aβ1-42 oligomers stimulate the p75NTR protein expression in the hippocampus through IGF-1R signaling. Thus, Aβ1-42 oligomers-mediated IGF-1R activation may trigger an increase in p75NTR protein expression in the hippocampus of AD brain during the early stages of disease development.
Molecular Signaling Group, National Research Council Canada, Institute for Biological Sciences, Ottawa, ON, Canada. ishingo@kumamoto-u.ac.jp
Shingo
S
Ito
Michel
M
Ménard
Trevor
T
Atkinson
Chantal
C
Gaudet
Leslie
L
Brown
James
J
Whitfield
Balu
B
Chakravarthy
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C075222:amyloid beta-protein (1-42); D017526:Receptor, IGF Type 1