title: Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease.
abstract: Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2(PP2A). In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2(PP2A) is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2(PP2A) translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2(PP2A), except when I2(PP2A) was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2(PP2A), inhibition of protein phosphatase 2A, and hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2(PP2A)-protein phosphatase 2A-Tau hyperphosphorylation pathway as a therapeutic target.
authors: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314-6399, USA.
authors: Gustavo
authors: G
authors: Basurto-Islas
authors: Inge
authors: I
authors: Grundke-Iqbal
authors: Yunn Chyn
authors: YC
authors: Tung
authors: Fei
authors: F
authors: Liu
authors: Khalid
authors: K
authors: Iqbal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*; D000099240:Asparaginyl Endopeptidase
chemical_list: D003546:Cysteine Endopeptidases; D054648:Protein Phosphatase 2; D016875:tau Proteins; D000099240:Asparaginyl Endopeptidase
keywords: Acidosis; Alzheimer Disease; I2PP2A; Legumain; Lysosomes; PP2A; SET; Tau; Tau Hyperphosphorylation
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