Granular expression of prolyl-peptidyl isomerase PIN1 is a constant and specific feature of Alzheimer’s disease pathology and is independent of tau, Aβ and TDP-43 pathology

Abstract

Alzheimer’s disease (AD) manifests with progressive memory loss and decline of spatial awareness and motor skills. Neurofibrillary tangles (NFTs) represent one of the pathological hallmarks of AD. Previous studies suggest that the enzyme prolyl-peptidyl cis–trans isomerase PIN1 [protein interacting with NIMA (never in mitosis A)-1] recognizes hyperphosphorylated tau (in NFTs) and facilitates its dephosphorylation, thereby recovering its function. This study aims to determine the frequency, severity and distribution of PIN1 immunoreactivity and its relationship to NFTs and other neuropathological markers of neurodegeneration such as amyloid-β (Aβ) plaques and transcription-responsive DNA-binding protein of Mr 43 kDa (TDP-43). Immunohistochemical analysis of 194 patients (46 with AD, 43 with Parkinson’s disease/dementia with Lewy bodies, 12 with progressive supranuclear palsy/corticobasal degeneration, 36 with frontotemporal lobar degeneration, 21 with motor neuron disease and 34 non-demented (ND) individuals) revealed an increased frequency and severity of PIN1 immunoreactive inclusions in AD as compared to all diagnostic groups (P < 0.001). The hippocampal and cortical distribution of PIN1 granules was distinct from that of NFTs, Aβ and TDP-43 pathologies, though the frequency of neurons with PIN1 immunoreactivity increased with increasing NFT pathology. There was a progressive increase in PIN1 changes in ND individuals as the degree of AD-type pathological changes increased. Present findings indicate that PIN1 changes are a constant feature of AD pathology and could serve as a biomarker of the onset or spread of AD neuropathology independent of tau or Aβ.

Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response

“…GVD lesions have also been described in the neocortex, hypothalamus, amygdala, and in the paramedian nuclei of the midbrain [37]. GVD-affected neurons were more frequently seen in Alzheimer's disease (AD) cases than in controls [3,14]. Other authors did not find such a correlation between GVD and AD when comparing AD cases with non-demented cases with AD-related pathology [46].…”

Hydroxynonenal-generated crosslinking fluorophore accumulation in Alzheimer disease reveals a dichotomy of protein turnover

“…Recent studies characterizing the GVD structure have been abundant, and a number of proteins have been found localized within them [36-39]. In addition to proteins, RNA and ribosomal proteins are also a substrate for HNE adduction [40, 41].…”

Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease

“…Recently, we observed a cytoplasmic granular localization of phosphorylated Smads in AD [9] which resembles the appearance of Pin1 positive granules [15,16]. Pin1 is a peptidyl-prolyl cis/trans isomerase which isomerizes specific Ser/Thr-Pro peptide bonds of target proteins after phosphorylation, thereby regulating their conformational state [17,18].…”