title: Differential accumulation of soluble amyloid beta peptides 1-40 and 1-42 in human monocytic and neuroblastoma cell lines. Implications for cerebral amyloidogenesis.
abstract: Alzheimer's disease (AD) is characterized by the massive deposition in the brain of the 40-42-residue amyloid beta protein (A(beta)). While A(beta)1-40 predominates in the vascular system, A(beta)1-42 is the major component of the senile plaques in the neuropil. The concentration of both A(beta) species required to form amyloid fibrils in vitro is micromolar, yet soluble A(betas) found in normal and AD brains are in the low nanomolar range. It has been recently proposed that the levels of A(beta) sufficient to trigger amyloidogenesis may be reached intracellularly. To study the internalization and intracellular accumulation of the major isoforms of A(beta), we used THP-1 and IMR-32 neuroblastoma cells as models of human monocytic and/or macrophagic and neuronal lineages, respectively. We tested whether these cells were able to internalize and accumulate 125I-A(beta)1-40 and 125I-A(beta)1-42 differentially when offered at nanomolar concentrations and free of large aggregates, conditions that mimic a prefibrillar stage of A(beta) in AD brain. Our results showed that THP-1 monocytic cells internalized at least 10 times more 125I-A(betas) than IMR-32 neuroblastoma cells, either isolated or in a coculture system. Moreover, 125I-A(beta)1-42 presented a higher adsorption, internalization, and accumulation of undigested peptide inside cells, as opposed to 125I-A(beta)1-40. These results support that A(beta)1-42, the major pathogenic form in AD, may reach supersaturation and generate competent nuclei for amyloid fibril formation intracellularly. In light of the recently reported strong neurotoxicity of soluble, nonfibrillar A(beta)1-42, we propose that intracellular amyloidogenesis in microglia is a protective mechanism that may delay neurodegeneration at early stages of the disease.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
authors.forename: L
authors.initials: L
authors.lastname: Morelli
authors.forename: M I
authors.initials: MI
authors.lastname: Prat
authors.forename: E M
authors.initials: EM
authors.lastname: Castaño
mesh_terms: D000327:Adsorption; D000544:Alzheimer Disease / Q000378:metabolism; D017772:Amyloid Neuropathies / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D007457:Iodine Radioisotopes / Q000032:analysis; D009000:Monocytes / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D020033:Protein Isoforms; C078592:amyloid beta-protein (1-40); C086839:amyloid beta-protein (17-42)