A conformation- and phosphorylation-dependent antibody recognizing the paired helical filaments of Alzheimer's disease.
Hyperphosphorylated tau (PHF-tau) is the major constituent of paired helical filaments (PHFs) from Alzheimer's disease (AD) brains. This conclusion has been based largely on the creation and characterization of monoclonal antibodies raised against PHFs, which can be classified in three categories: (a) those recognizing unmodified primary sequences of tau, (b) those recognizing phosphorylation-dependent epitopes on tau, and (c) those recognizing conformation-dependent epitopes on tau. Recent studies have suggested that the antibodies recognizing primary sequence and phosphorylation-dependent epitopes on tau are unable to distinguish between normal adult biopsy tau and PHF-tau. We now present evidence for a new fourth class of monoclonal antibodies recognizing conformation-dependent phosphoepitopes on tau, typified by TG-3, a monoclonal antibody raised to PHFs from AD brain homogenates. Studies using a series of deletional tau mutants, site-directed tau mutants, and synthetic peptides enable the precise epitope mapping of TG-3. Additional studies demonstrate that TG-3 reacts with neonatal mouse tau and PHF-tau but does not recognize adult mouse tau or tau derived from normal human autopsy or biopsy tissue. Further investigation reveals that TG-3 recognizes a unique conformation of tau found almost exclusively in PHFs from AD brains.
Jicha
G A
GA
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, U.S.A.
Lane
E
E
Vincent
I
I
Otvos
L
L
Hoffmann
R
R
Davies
P
P
D000328:Adult; D000544:Alzheimer Disease / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001921:Brain / Q000166:cytology / Q000473:pathology*; D018891:Dentate Gyrus / Q000166:cytology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016253:Microscopy, Immunoelectron; D008870:Microtubules / Q000473:pathology* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000473:pathology* / Q000648:ultrastructure; D010766:Phosphorylation; D011487:Protein Conformation; D017966:Pyramidal Cells / Q000166:cytology / Q000473:pathology; D011994:Recombinant Proteins / Q000032:analysis; D016875:tau Proteins / Q000032:analysis* / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D016875:tau Proteins