Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex.
The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by beta-amyloid peptide (Abeta) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Abeta peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.
Peel
Alyson L
AL
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Sorscher
Noah
N
Kim
Joseph Y
JY
Galvan
Veronica
V
Chen
Sylvia
S
Bredesen
Dale E
DE
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002460:Cell Line; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010766:Phosphorylation; D012720:Severity of Illness Index; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human