The severity of cortical Alzheimer's type changes is positively correlated with increased amyloid-β Levels: Resolubilization of amyloid-β with transition metal ion chelators

Abstract

The most consistent diagnostic neuropathological lesion in Alzheimer's disease (AD) is the senile plaque of which the 4 kD amyloid-β (Aβ) peptide is the major proteinaceous component. In this study cortical Aβ levels were immunochemically measured in 70 post-mortem human brains and compared against their neuropathological grading as determined by the densities of amyloid plaques and neurofibrillary tangles. The mean concentration of cortical Aβ/mg protein increased with the severity of the cortical degenerative changes (AD0 < AD1 < AD2 < AD3). Brains with the severe degenerative changes (AD3), corresponded to definite AD cases and exhibited significantly increased concentrations of Aβ (11.1 ± 3.08 ng/mg total protein, n=17) when compared with control brains without any degenerative changes (AD0; 0.06 ± 0.06 ng/mg total protein, n=14, P=0.003). The extraction of Aβ from the cortex of AD3 brains was significantly enhanced in a dose dependent manner by the presence of the metal ion chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (5 mM TPEN, P < 0.0001). The chelator/antioxidant 1,2-dithiolane-3-pentanoic acid (lipoic acid), also resolubilized Aβin a dose-dependant manner. Both chelators also enhanced the extraction of Aβ from the frontal cortex of AβPP-transgenic mice suggesting this animal model of amyloidosis may be useful for evaluating the biochemical and therapeutic effects of chelators/antioxidants on Aβ deposition. In summary our results indicate that increased Aβ load is correlated with the severity of the cortical AD-type changes and that chelators/antioxidants may be useful in reducing neuronal amyloid burden.