Characterization of the toxic mechanism triggered by Alzheimer's amyloid‐β peptides via p75 neurotrophin receptor in neuronal hybrid cells

Abstract

Neuronal pathology of the brain with Alzheimer's disease (AD) is characterized by numerous depositions of amyloid-beta peptides (Abeta). Abeta binding to the 75-kDa neurotrophin receptor (p75NTR) causes neuronal cell death. Here we report that Abeta causes cell death in neuronal hybrid cells transfected with p75NTR, but not in nontransfected cells, and that p75NTR(L401K) cannot mediate Abeta neurotoxicity. We analyzed the cytotoxic pathway by transfecting pertussis toxin (PTX)-resistant G protein alpha subunits in the presence of PTX and identified that Galpha(o), but not Galpha(i), proteins are involved in p75NTR-mediated Abeta neurotoxicity. Further investigation suggested that Abeta neurotoxicity via p75NTR involved JNK, NADPH oxidase, and caspases-9/3 and was inhibited by activity-dependent neurotrophic factor, insulin-like growth factor-I, basic fibroblast growth factor, and Humanin, as observed in primary neuron cultures. Understanding the Abeta neurotoxic mechanism would contribute significantly to the development of anti-AD therapies.

Molecular characterization of neurohybrid cell death induced by Alzheimer's amyloid‐β peptides via p75NTR/PLAIDD

“…L401K-p75NTR is unable to couple with Go protein. When F11 cells transfected with L401K-p75NTR cDNA were treated with 10 lM Ab(1-42), induction of cell death was not observed, as has been reported earlier (Tsukamoto et al 2003). Likewise, transfection of PLAIDD cDNA followed by treatment of 10 lM Ab(1-42) did not induce cell death at all.…”

“…This pathway, mediated by p75NTR, PLAIDD, Gi, JNK, NADPH oxidase, and caspase3-related caspases, is distinct from the pathway by p75NTR, Go, JNK, NADPH oxidase, and caspase3-related caspases that has been elucidated in Ab toxicity mediated by p75NTR (Tsukamoto et al 2003).…”

“…Upon activation by ligands, death domains of TNFR and Fas transmit death signals. Likewise, it has been reported that NGF binding to p75NTR induces apoptosis (Kong et al 1999;Wang et al 2001;Tsukamoto et al 2003). Based on the structural characteristics shared between p75NTR and TNFRI or Fas (Feinstein and Larhmmer 1990), it is considered that p75NTR belongs to a death receptor family with the type II death domain, and TNFRI and Fas belong to a death receptor family with the type I.…”

“…p75NTR mediates Ab neurotoxicity 2. L401K-p75NTR, a p75NTR mutant which cannot interact with a heterotrimeric Go protein, loses this function 3. p75NTR-mediated Ab neurotoxicity most likely involves Go, JNK, NADPH oxidase and caspases-3/9 (Tsukamoto et al 2003).…”

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…A previous report supports this concept, demonstrating that A␤-derived diffusible ligands (ADDLs) potently alter NGF-mediated signaling in cultured cells [30]. Moreover, several studies suggested that A␤ toxicity is produced through the association with p75NTR [31][32][33][34][35][36][37]. Specifically, A␤ toxicity mediated by p75NTR depends on a death domain [38] in the cytoplasmic part of p75NTR molecules [37].…”