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.