Amyloid-beta peptides stimulate the expression of the p75(NTR) neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice.
The progression toward end-stage Alzheimer's disease (AD) in the aging brain is driven by accumulating amyloid-beta (Abeta)(1-42) oligomers that is accompanied by the downregulation of the Trk A neurotrophin receptor and by either upregulation or at least maintenance of the p75 neurotrophin receptor (p75(NTR)), which can be stimulated by the accumulating Abeta(1-42) peptides. Here we show that Abeta(1-42) and its active fragment Abeta(25-35), but not Abeta(42-1), can at least double the level of p75(NTR) receptors in the membranes of model SH-SY5Y human neuroblastoma cells. We also show that p75(NTR) is upregulated in the hippocampi of two strains of AD transgenic mice. Specifically, the level of the p75(NTR) receptor in the hippocampal membranes from 12-15 month old AD-triple transgenic mice (3xTg-AD) harboring PS1 (M146V), AbetaPP (Swe), and tau (P301L) was nearly twice that in hippocampal membranes from age-matched wild-type mice. Similarly, the level of p75 (NTR) receptor in 7 month-old B6.Cg-Tg AD mice harboring PSEN1dE9 and AbetaPP (Swe) was also increased above the level in the corresponding wild-type mice. This increase correlated with the age-dependent rise in Abeta(1-42) levels in the AD mice. Thus, it appears that it could be the accumulating Abeta(1-42) that increases or at least prevents the downregulation of p75 (NTR) receptors in key parts of AD brains. It is possible that when the Abeta (1-42) accumulation reaches a critical level in the brain on the way to late-onset AD, the Abeta (1-42) induced p75 (NTR) receptor signaling starts a vicious cycle that accelerates AD development because of the activated receptors' recently shown ability to stimulate Abeta(1-42) production.
National Research Council Canada, Institute for Biological Sciences, Ottawa, ON, Canada. Balu.Chakravarthy@nrc-cnrc.gc.ca
Balu
B
Chakravarthy
Chantal
C
Gaudet
Michel
M
Ménard
Trevor
T
Atkinson
Leslie
L
Brown
Frank M
FM
Laferla
Ubaldo
U
Armato
James
J
Whitfield
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D053764:Presenilin-1 / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020800:Receptor, Nerve Growth Factor