The emerging role of peptidyl‐prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease

Peptidyl‐prolyl cis/trans isomerases (PPIases), a unique family of molecular chaperones, regulate protein folding at proline residues. These residues are abundant within intrinsically disordered proteins, like the microtubule‐associated protein tau. Tau has been shown to become hyperphosphorylated and accumulate as one of the two main pathological hallmarks in Alzheimer's disease, the other being amyloid beta (Aβ). PPIases, including Pin1, FK506‐binding protein (FKBP) 52, FKBP51, and FKBP12, have been shown to interact with and regulate tau biology. This interaction is particularly important given the numerous proline‐directed phosphorylation sites found on tau and the role phosphorylation has been found to play in pathogenesis. This regulation then affects downstream aggregation and oligomerization of tau. However, many PPIases have yet to be explored for their effects on tau biology, despite the high likelihood of interaction based on proline content. Moreover, Pin1, FKBP12, FKBP52, cyclophilin (Cyp) A, CypB, and CypD have been shown to also regulate Aβ production or the toxicity associated with Aβ pathology. Therefore, PPIases directly and indirectly regulate pathogenic protein multimerization in Alzheimer's disease and represent a family rich in targets for modulating the accumulation and toxicity. Here, we summarize what is known about peptidyl‐prolyl cis/trans isomerases (PPIases) in Alzheimer's disease and discuss their potential utility for therapeutic development and gaining mechanistic insights. The tau protein contains more than 40 proline residues while the amyloid precursor protein contains critical proline residues that lead to amyloid formation. Prolines help control protein phosphorylation, but they also play a very important role in protein structure. We discuss this latter function and the potential role of the ~ 36 PPIases in Alzheimer's pathobiology. Here, we summarize what is known about peptidyl‐prolyl cis/trans isomerases (PPIases) in Alzheimer's disease and discuss their potential utility for therapeutic development and gaining mechanistic insights. The tau protein contains more than 40 proline residues while the amyloid precursor protein contains critical proline residues that lead to amyloid formation. Prolines help control protein phosphorylation, but they also play a very important role in protein structure. We discuss this latter function and the potential role of the ~ 36 PPIases in Alzheimer's pathobiology.