Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations.
Several recent studies support a link between tau protein phosphorylation and adduction of tau by reactive carbonyls. Indeed, the phosphorylation-dependent adduction of tau by carbonyl products resulting from lipid peroxidation creates the neurofibrillary tangle-related antigen, Alz50. To determine whether epitopes of carbonyl-modified tau are major conformational changes associated with neurofibrillary tangle formation, we examined seven distinct antibodies raised against neurofibrillary tangles that recognize unique epitopes of tau in Alzheimer disease. Consistently, all seven antibodies recognize tau more strongly (4- to 34-fold) after treatment of normal tau with the reactive carbonyl, 4-hydroxy-2-nonenal (HNE), but only when tau is in the phosphorylated state. These findings not only support the idea that oxidative stress is involved in neurofibrillary tangle formation occurring in brains of Alzheimer disease patients, but also show, for the first time, that HNE modifications of tau promote and contribute to the generation of the major conformational properties defining neurofibrillary tangles.
Liu
Quan
Q
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Smith
Mark A
MA
Avilá
Jesus
J
DeBernardis
John
J
Kansal
Mayank
M
Takeda
Atsushi
A
Zhu
Xiongwei
X
Nunomura
Akihiko
A
Honda
Kazuhiro
K
Moreira
Paula I
PI
Oliveira
Catarina R
CR
Santos
Maria S
MS
Shimohama
Shun
S
Aliev
Gjumrakch
G
de la Torre
Jack
J
Ghanbari
Hossein A
HA
Siedlak
Sandra L
SL
Harris
Peggy L R
PL
Sayre
Lawrence M
LM
Perry
George
G
D000368:Aged; D000369:Aged, 80 and over; D000447:Aldehydes / Q000737:chemistry; D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D051379:Mice; D008957:Models, Genetic; D018384:Oxidative Stress; D010766:Phosphorylation; D011487:Protein Conformation; D013997:Time Factors; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
D000447:Aldehydes; D000939:Epitopes; D016875:tau Proteins; C027576:4-hydroxy-2-nonenal