Configuration-specific immunotherapy targeting cis pThr231-Pro232 tau for Alzheimer disease.

Tau pathology is the main pathological characteristic of mild cognitive impairment (MCI) and Alzheimer disease (AD), and tau-based therapeutic strategies have great implications in the prevention of MCI and AD. The phosphorylation of threonine 231 preceding proline 232 (pThr231-Pro232) triggers tau hyperphosphorylation, tau aggregation, and tau pathology. Interestingly, the pThr231-Pro232 motif may be in a cis or trans configuration, but several recent studies have firstly indicated that cis, but not trans, pThr231-Pro232 tau is a striking therapeutic target for MCI and AD. Cis pThr231-Pro232 tau appears firstly in MCI and accumulates exclusively in the development of AD. Moreover, cis pThr231-Pro232 tau has low affinity to microtubules, high resistance to dephosphorylation and degradation, and a potent tendency to aggregate. On the contrary, trans pThr231-Pro232 tau has normal physiological activity in vivo. Fortunately, Pin1 is the only known isomerase that catalyzes pThr231-Pro232 tau from the neurotoxic cis to nontoxic trans configuration, which prevents MCI and AD. Nonetheless, as we have mentioned before, Pin1 is frequently inactivated under abnormal physiological conditions in vivo. Therefore, it is necessary to clear cis pThr231-Pro232 tau by immunotherapy when Pin1 is insufficient, in order to avoid the occurrence of MCI and AD.