Relative expression of the p75 neurotrophin receptor, tyrosine receptor kinase A, and insulin receptor in SH-SY5Y neuroblastoma cells and hippocampi from Alzheimer's disease patients.
We have previously shown in SH-SY5Y human neuroblastoma cells that the expressions of basal (75 kDa) and high molecular weight (HMW; 85 kDa) isoforms of the p75 neurotrophic receptor (p75NTR) are stimulated by amyloid-β peptide1-42 oligomers (AβOs) via the insulin-like growth factor-1 receptor (IGF-1R). On the other hand, it is known that AβOs inhibit insulin receptor (IR) signaling. The purpose of the present study was to determine the involvement of IR signaling in the regulation of p75 neurotrophin receptor (p75NTR) protein isoform expression in cultured SH-SY5Y cells and in hippocampi from late-stage human Alzheimer's disease (AD) brains. Interestingly, insulin induced the expression of basal and HMW p75NTR isoforms in SH-SY5Y cells, suggesting the presence of cross-talk between the IR and IGF-1R for the regulation of p75NTR expression. Reducing IR signaling with an IR kinase inhibitor (AG 1024) or IR-targeted siRNAs increased HMW p75NTR expression and reduced tyrosine receptor kinase-A (Trk-A) expression as well as postsynaptic density protein 95 (PSD95) expression in SH-SY5Y cells. Both basal and HMW p75NTR isoforms were increased in the hippocampi of post-mortem late-stage human AD brains (relative to non-AD brains), and the protein expression of HMW p75NTR was negatively associated with Trk-A expression, PSD95 expression, and IR expression. Thus, increased p75NTR expression, specifically an increased p75NTR-to-Trk-A ratio, is likely to play a role in synaptic loss and neuronal cell death in late-stage AD. Collectively, these findings suggest that increased expression of the p75NTR due to IR signaling inhibition by AβOs might be involved in the pathology of AD.
Faculty of Life Sciences, Department of Pharmaceutical Microbiology, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. Electronic address: ishingo@kumamoto-u.ac.jp.
Shingo
S
Ito
Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.
Michel
M
Ménard
Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.
Trevor
T
Atkinson
Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.
Leslie
L
Brown
Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.
James
J
Whitfield
Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.
Balu
B
Chakravarthy
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D045744:Cell Line, Tumor; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D011972:Receptor, Insulin
Alzheimer disease; Insulin receptor; Insulin-like growth factor-1 receptor; PSD95; p75 neurotrophin receptor; tyrosine receptor kinase-A