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

Abstract

One of the most important pathological features of Alzheimer's disease (AD) is extracellular senile plaques, whose major component is amyloid-b peptides (Ab). Ab binds to the extracellular domain of p75NTR (p75 neurotrophin receptor) and induces neuronal cell death. We investigated the molecular mechanism of Ab-induced neurotoxicity in detail from the standpoint of interaction between p75NTR and its recently identified relative, PLAIDD (p75-like apoptosis-inducing death domain). Using F11 neuronal hybrid cells, we demonstrate that there are two distinct pathways for Abinduced toxicity mediated by p75NTR. One pathway that has been previously elucidated, is mediated by p75NTR, Go, JNK, NADPH oxidase and caspase3-related caspases. We found that PLAIDD and Gi proteins, heterotrimeric G proteins, are involved in the alternative Ab-induced neurotoxicity mediated by p75NTR. The alternative pathway triggered by Ab is thus mediated by p75NTR, PLAIDD, Gi, JNK, NADPH oxidase and caspase3-related caspases. In addition, we found that HN, ADNF, IGF-I, or bFGF inhibits both pathways of Ab-induced neurotoxicity mediated by p75NTR. Amyloid-b peptides (Ab) are the major constituent of the senile plaques in Alzheimer's disease (AD). Ab, the 39-43 amino acids peptide, is produced by the b-and c-secretasemediated cleavage of amyloid precursor protein (APP). Formation and accumulation of Ab have been inferred to contribute to the development of AD. In vitro, increased levels of Ab concentration cause cell death in primary cultured neurons as well as some neuronal line cells (Yankner et al. 1989;Loo et al. 1993;Gschwind and Huber 1995;Kaneko et al. 1995;Pike et al. 1997;Giovanni et al. 1999;Sudo et al. 2001). However, the precise mechanism underlying Ab neurotoxicity remains to be elucidated.One possible mechanism for Ab-induced neurotoxicity is that Ab binds to its putative receptor on the neuronal cell membrane and triggers the intracellular death signal. Multiple proteins have been so far claimed to be candidates for the Ab receptor. They include the receptors for the endoplasmic reticulum Ab-binding dehydrogenase (ERAB;Yan et al. 1997a), the advanced glycation end products (Yan et al. 1997b), the a7 nicotinic acetylcholine receptor (Wang Address correspondence and reprint requests to M. Matsuoka, Department of Pharmacology, KEIO University School of Medicine, Shinanomachi, Tokyo, Japan. E-mail: sakimatu@sc.itc.keio.ac.jpAbbreviations used: Ab, amyloid beta; AD, Alzheimer's disease; ADNF, activity-dependent neurotrophic factor; APO, apocynin; APP, amyloid precursor protein; BBP-1, b-amyloid binding protein-1; bFGF, basic fibroblast growth factor; DPI, diphenyleneiodonium chloride; ERAB, endoplasmic reticulum Ab-binding dehydogenase; FBS, fetal bovine serum; GEE, gluthione-ethyl-ester; HN, Humanin; HRP, horseradish peroxidase; JNK, c-Jun N-terminal kinase; NFkB, nuclear factorkB; NOS, nitric oxide synthase; (p75-like apoptosis-inducing death domain) p75NTR, 75 kDa neurotrophin receptor; PTX, pertussis toxin; ROS, reactive ox...

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