title: p75NTR is mainly responsible for Aβ toxicity but not for its internalization: a primary study.
abstract: Accumulating evidence indicates that the intraneuronal accumulation of beta-amyloid peptide (Aβ) is earlier than the formation of extraneuronal amyloid plaque but the mechanism of the accumulation remains unclear. p75NTR is a receptor for Aβ and interacts with Aβ in vitro and in vivo but whether p75NTR mediates Aβ internalization and intraneuronal accumulation is not known. In this study, we aim to determine if p75NTR mediates Aβ internalization, which might provide new insights into Aβ metabolism and toxicity. FRET analysis in PC12 cells showed that internalized Aβ was close to p75NTR. Aβ1-42 could be internalized in PC12 cells in a concentration-dependent manner but the antibody to the p75NTR extracellular domain did not prevent its internalization. Aβ1-42 could also be internalized in mouse neonatal cortical neurons and the deletion of p75NTR in these neurons did not prevent its internalization but prevented Aβ neurotoxicity. Cholesterol at 10 μM significantly increased Aβ1-42 internalization in PC12 cells. Internalized Aβ1-42 is mainly co-localized with Beclin-1 (a biomarker of autophagosomes) but not with endosomal and lysomal markers. p75NTR may not play a main role in Aβ internalization at the concentrations tested but is responsible for Aβ induced toxicity in primary neurons. Internalized Aβ is mainly sorted to autophagosomes for metabolism.
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide 5001, Australia. yuhlzjl@ccmu.edu.cn
authors.forename: Huanling
authors.initials: H
authors.lastname: Yu
authors.forename: Miao
authors.initials: M
authors.lastname: Yang
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Xiao
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C068313:Ngfr protein, rat