Intraneuronal Aβ accumulation in Alzheimer's disease

Abstract

A key question in understanding Alzheimer's disease (AD) is whether extracellular Aβ deposition as parenchymal amyloid plaques or intraneuronal Aβ accumulation initiates the AD process which is characterized first by synaptic alteration followed by an undefined series of events that lead to neuronal degeneration. It is currently thought that full length amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce soluble Aβ which is then released into the brain interstitial fluid. The intraneuronal Aβ accumulation is hypothesized to predominate from the neuronal uptake of this soluble extracellular Aβ rather than from ER/Golgi processing of APP. Understanding the mechanism of neuronal uptake of Aβ might lead to potential therapeutic targets that could minimize this uptake and the subsequent neurodegeneration that leads to the development of dementia. In this study, we demonstrate that substitution of the two adjacent histidine residues of Aβ40 results in a significant decrease in its uptake in differentiated PC12 cells as measured by flow cytometry of fluorscein-labeled Aβ derivatives. These substitutions also result in a dramatic enhancement of both thioflavin-T measured fibril formation and binding to the Aβ fibrils assessed by surface plasmon resonance while maintaining its ability to bind to amyloid plaques. Hence, alteration of the histidine domain of Aβ prevented neuronal uptake and drove Aβ to enhanced fibril formation and subsequent amyloid plaque deposition - a potential mechanism for removing toxic species of Aβ. Substitution or even masking of these histidine residues of Aβ might provide a new therapeutic direction for minimizing neuronal uptake and subsequent neuronal degeneration and maximizing targeting to amyloid plaques. In addition, such derivatives should facilitate their use for the molecular imaging of amyloid plaques for the early diagnosis of AD.