The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging.
The abundance and solubility of Abeta peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total Abeta1-40 and Abeta1-42 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 Abeta1-40 and Abeta1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, we first demonstrated that each assay is specific for Abeta1-40 or Abeta1-42 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 Abeta1-40 and Abeta1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble Abeta1-40 were increased 20-fold while the average levels of insoluble Abeta1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of Abeta1-40 and Abeta1-42 were the largest fractions of total Abeta 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 Abeta1-40 and Abeta1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble Abeta1-40 plays mechanistic roles in the onset and/or progression of AD.
Division of Anatomic Pathology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
J
J
Wang
D W
DW
Dickson
J Q
JQ
Trojanowski
V M
VM
Lee
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000911:Antibodies, Monoclonal; D052160:Benzothiazoles; D001921:Brain / Q000166:cytology / Q000473:pathology*; D001923:Brain Chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis*; D058225:Plaque, Amyloid / Q000473:pathology; D012016:Reference Values; D012995:Solubility; D013844:Thiazoles / Q000032:analysis
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T