TY - JOUR
T1 - The severity of cortical Alzheimer's type changes is positively correlated with increased amyloid-β levels
T2 - Resolubilization of amyloid-β with transition metal ion chelators
AU - Fonte, Justin
AU - Miklossy, Judith
AU - Atwood, Craig
AU - Martins, Ralph
PY - 2001
Y1 - 2001
N2 - The most consistent diagnostic neuropathological lesion in Alzheimer's disease (AD) is the senile plaque of which the 4 kD amyloid-β peptide is the major proteinaceous component. In this study cortical Aβ levels were immuno-chemically 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 (ADO < ADI < 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 (ADO; 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 Aβ in 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.
AB - The most consistent diagnostic neuropathological lesion in Alzheimer's disease (AD) is the senile plaque of which the 4 kD amyloid-β peptide is the major proteinaceous component. In this study cortical Aβ levels were immuno-chemically 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 (ADO < ADI < 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 (ADO; 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 Aβ in 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.
UR - http://www.scopus.com/inward/record.url?scp=0034987999&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:0034987999
VL - 3
SP - 209
EP - 219
JO - Journal of Alzheimer's disease : JAD
JF - Journal of Alzheimer's disease : JAD
SN - 1387-2877
IS - 2
ER -