Differential Effects of Alzheimer's Disease Aβ40 and 42 on Endocytosis and Intraneuronal Trafficking

Anomalous neuronal accumulation of A beta peptides was shown to affect synaptic transmission and contribute to neurodegeneration in Alzheimer's disease (AD) brain. Neuronal cells internalize amyloid beta (A beta) peptides from the brain extracellular space even under normal physiological conditions, and these endocytotic pathways go awry during AD progression. We hypothesized that exposure to toxic A beta species accumulating in AD brain contributes to perturbations in neuronal endocytosis. We have shown substantial down-regulation of KEGG endocytotic pathway genes in AD patient brain regions that accumulate A beta compared to those in non-demented individuals. While both A beta 40 and A beta 42 perturbed endocytosis and intracellular trafficking in neuronal cells, A beta 40 had a greater effect than A beta 42. Moreover, A beta 40 decreased the neuronal uptake and lysosomal accumulation of A beta 42, which tends to oligomerize at low lysosomal pH. Hence, A beta 40 may reduce the prevalence of stable A beta 42 oligomers that are closely associated with neurodegeneration and are intercellularly propagated across the vulnerable brain regions to eventually nucleate as amyloid plaques. In conclusion, elevated brain A beta levels and A beta 42:40 ratio apparent in the early stages of AD could perturb intraneuronal trafficking, augment the anomalous accumulation of amyloid peptides in AD brain, and drive AD pathogenesis. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.