Affiliations: [a] Molecular Signalling Group, National Research Council Canada, Institute for Biological Sciences, Ottawa, ON, Canada | [b] Department of Neurobiology and Behavior, University of California, Irvine, CA, USA | [c] Histology and Embryology Unit, Department of Biomedical and Surgical Sciences, University of Verona Medical School, Verona, Italy
Correspondence:
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Correspondence to: Dr. Balu Chakravarthy, National Research Council, 1200 Montreal Rd., Bldg M-54, Institute for Biological Sciences, Ottawa, ON, Canada K1A 0R6. Tel.: +1 613 990 0899; Fax: +1 613 941 4475; E-mail: [email protected].
Abstract: The progression toward end-stage Alzheimer's disease (AD) in the aging brain is driven by accumulating amyloid-β (Aβ)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 (p75NTR), which can be stimulated by the accumulating Aβ1-42 peptides. Here we show that Aβ1-42 and its active fragment Aβ25-35, but not Aβ42-1, can at least double the level of p75NTR receptors in the membranes of model SH-SY5Y human neuroblastoma cells. We also show that p75NTR is upregulated in the hippocampi of two strains of AD transgenic mice. Specifically, the level of the p75NTR receptor in the hippocampal membranes from 12–15 monthold AD-triple transgenic mice (3xTg-AD) harboring PS1M146V, AβPPSwe, and tauP301L was nearly twice that in hippocampal membranes from age-matched wild-type mice. Similarly, the level of p75NTR receptor in 7 month-old B6.Cg-Tg AD mice harboring PSEN1dE9 and AβPPSwe was also increased above the level in the corresponding wild-type mice. This increase correlated with the age-dependent rise in Aβ1-42 levels in the AD mice. Thus, it appears that it could be the accumulating Aβ1-42 that increases or at least prevents the downregulation of p75NTR receptors in key parts of AD brains. It is possible that when the Aβ1-42 accumulation reaches a critical level in the brain on the way to late-onset AD, the Aβ1-42-induced p75NTR receptor signaling starts a vicious cycle that accelerates AD development because of the activated receptors' recently shown ability to stimulate Aβ1-42 production.
Keywords: Alzheimer's disease, amyloid-β peptides, human neuroblastomas, p75NTR (neurotrophin receptor), SH-SY5Y human neuroblastomas, transgenic mice
