Differential accumulation of soluble amyloid beta peptides 1-40 and 1-42 in human monocytic and neuroblastoma cell lines - Implications for cerebral amyloidogenesis

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 speci es required to form amyloid fibrils in vitro is micromolar, yet soluble A b eta s 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 amyl oidogenesis may be reached intracellularly. To study the internalization an d intracellular accumulation of the major isoforms of A beta, we used THP-I and IMR-32 neuroblastoma cells as models of human monocytic and/or macroph agic and neuronal lineages, respectively. We tested whether these cells wer e able to internalize and accumulate I-125-A beta 1-40 and I-125-A beta 1-4 2 differentially when offered at nanomolar concentrations and free of large aggregates, conditions that mimic a prefibrillar stage of A beta in AD bra in. Our results showed that THP-1 monocytic cells internalized at least 10 times more I-125-A beta s than IMR-32 neuroblastoma cells, either isolated or in a coculture system. Moreover, I-125-A beta 1-42 presented a higher ad sorption, internalization, and accumulation of undigested peptide inside ce lls, as opposed to I-125-A beta 1-40. These results support that A beta 1-4 2, 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 prote ctive mechanism that may delay neurodegeneration at early stages of the dis ease.