TY - JOUR
T1 - The levels of soluble versus insoluble brain aβ distinguish Alzheimer's disease from normal and pathologic aging
AU - Wang, Jun
AU - Dickson, Dennis W.
AU - Trojanowski, John Q.
AU - Lee, Virginia M.Y.
N1 - Funding Information:
The authors thank Takeda Chemical Industries (Dr. N. Suzuki) for providing critical antibody reagents, as well as Dr. A. Kathakali, Dr. D. Leonard, Dr. M. L. Schmidt, Ms. S. Leight, Mr. T.-S. Chiu, and our colleagues in the Departments of Neurology, Pathology, and Laboratory Medicine and Psychiatry for their help with many aspects of this study. This research was supported in part by grants from the National Institute on Aging of the National Institutes of Health and from the Charles A. Dana Foundation. Finally, we express our appreciation to the families of the patients studied here for making our work possible through their generous efforts to foster research.
PY - 1999/8
Y1 - 1999/8
N2 - The abundance and solubility of Aβ peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total Aβ1-40 and Aβ1-42 in AD brains with those in age-matched normal and pathologic aging brains using a sandwich enzyme-linked immunosorbent assay (ELISA). Since the measurement of Aβ1-40 and Aβ1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, we first demonstrated that each assay is specific for Aβ1-40 or Aβ1-42 and the levels of these peptides are not affected by the amyloid precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to show that the average levels of total cortical soluble and insoluble Aβ1-40 and Aβ1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble Aβ1-40 were increased 20-fold while the average levels of insoluble Aβ1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of Aβ1-40 and Aβ1-42 were the largest fractions of total Aβ in the normal brain (i.e., 50 and 23%, respectively), but they were the smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data suggest that pathologic aging is a transition state between normal aging and AD. More importantly, our findings imply that a progressive shift of brain Aβ1-40 and Aβ1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble Aβ1-40 plays mechanistic roles in the onset and/or progression of AD.
AB - The abundance and solubility of Aβ peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total Aβ1-40 and Aβ1-42 in AD brains with those in age-matched normal and pathologic aging brains using a sandwich enzyme-linked immunosorbent assay (ELISA). Since the measurement of Aβ1-40 and Aβ1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, we first demonstrated that each assay is specific for Aβ1-40 or Aβ1-42 and the levels of these peptides are not affected by the amyloid precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to show that the average levels of total cortical soluble and insoluble Aβ1-40 and Aβ1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble Aβ1-40 were increased 20-fold while the average levels of insoluble Aβ1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of Aβ1-40 and Aβ1-42 were the largest fractions of total Aβ in the normal brain (i.e., 50 and 23%, respectively), but they were the smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data suggest that pathologic aging is a transition state between normal aging and AD. More importantly, our findings imply that a progressive shift of brain Aβ1-40 and Aβ1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble Aβ1-40 plays mechanistic roles in the onset and/or progression of AD.
KW - Amyloid plaques
KW - Amyloidosis
KW - Aβ peptide
KW - Heterogeneity.
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U2 - 10.1006/exnr.1999.7085
DO - 10.1006/exnr.1999.7085
M3 - Article
C2 - 10415140
AN - SCOPUS:0032837741
SN - 0014-4886
VL - 158
SP - 328
EP - 337
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -