Distinct functions of cis and trans phosphorylated tau in Alzheimer's disease and their therapeutic implications

Proline-directed protein phosphorylation (pSer/Thr-Pro), a central signaling mechanism in diverse cellular processes in physiology and disease, has been proposed to be subject to further cis-trans conformational regulation by the unique prolyl isomerase Pin1. Until recently, no tool is available to directly detect the cis-trans conformation of Pin1-catalyzed cis-trans conformational changes in vivo. We have developed novel peptide chemistry that enables to generate the first antibodies that can distinguish cis from trans pThr231-Pro conformation in tau (p-tau). Using these conformation-specific antibodies, we have discovered that cis, but not trans, p-tau appears early in mild cognitive impairment (MCI) neurons and further accumulates in neurofibrillary degenerated neurons as Alzheimer's disease (AD) progresses, localizing to the dystrophic neurites, an early hallmark change that correlates with synaptic and cognitive deficits. Unlike trans p-tau, the cis not only cannot promote microtubule assembly, but also is more resistant to dephosphorylation and degradation, and prone to aggregation. Pin1 accelerates cis to trans conversion to prevent the accumulation of the pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. These findings develop the first tool to directly detect cis-trans prolyl isomerization, especially after phosphorylation and uncover cis p-tau as the very early pathogenic conformation leading to tau pathology and memory loss in AD. These results also suggest novel conformation-specific diagnoses and therapies for AD and likely others.