HH Domain of Alzheimer's Disease Aβ Provides Structural Basis for Neuronal Binding in PC12 and Mouse Cortical/Hippocampal Neurons

A key question in understanding AD is whether extracellular A beta deposition of parenchymal amyloid plaques or intraneuronal A beta accumulation initiates the AD process. Amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce soluble A beta which is then released into the brain interstitial fluid. Intraneuronal A beta accumulation is hypothesized to predominate from the neuronal uptake of this soluble extracellular A beta rather than from ER/Golgi processing of APP. We demonstrate that substitution of the two adjacent histidine residues of A beta 40 results in a significant decrease in its binding with PC12 cells and mouse cortical/hippocampal neurons. These substitutions also result in a dramatic enhancement of both thioflavin-T positive fibril formation and binding to preformed A beta fibrils while maintaining its plaque-binding ability in AD transgenic mice. Hence, alteration of the histidine domain of A beta prevented neuronal binding and drove A beta to enhanced fibril formation and subsequent amyloid plaque deposition - a potential mechanism for removing toxic species of A beta. Substitution or even masking of these A beta histidine residues might provide a new therapeutic direction for minimizing neuronal uptake and subsequent neuronal degeneration and maximizing targeting to amyloid plaques.