Increased frequency and severity of PIN1 pathology in Alzheimer's disease and other related dementias

One of the pathological hallmarks of Alzheimer's disease (AD) is the intraneuronal accumulation of hyperphosphorylated tau proteins, in the form of neurofibrillary tangles (NFTs). NFTs also occur in non-AD dementias including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and in some cases of frontotemporal lobar degeneration (FTLD). Whereas hyperphosphorylation of tau causes microtubule disassembly and distorts the neuronal cytoskeleton, the enzyme prolyl-peptidyl cis-trans isomerase PIN1 (protein interacting with NIMA (never in mitosis A)-1) targets specific phosphorylated motifs on tau, facilitating its dephosphorylation and restoring its ability to promote microtubule assembly. Immunohistochemical analysis of PIN1 in hippocampal and neocortical sections was applied in 135 dementia cases (37 of AD, 43 of PD/DLB, 12 of PSP/CBD, 35 of FTLD, 10 of motor neuron disease (MND)). Using light microscopy, PIN1 pathology was rated in 9 regions of the cerebral cortex and hippocampus according to a 5-point scale; the overall PIN1 severity score in each case being the summation of subregional scores. PIN1-immunopositive granules were present in 62% of the total study population, including 100% of AD, 79% of PD and DLB, 67% of PSP and CBD, 15% of FTLD, and 18% of MND cases. The higher frequency of PIN1 in AD and lower frequency in FTLD and MND resulted in a significant frequency difference between groups (p < 0.001). Mean PIN1 overall severity scores (AD = 9.2, PD/DLB = 2.6, PSP/CBD = 3.5, FTLD = 0.5 and MND = 0.8) were significantly different across all groups (P PD/DLB and PSP/CBD > FTLD/MND. In addition, subregional hippocampal distribution of PIN1 differed hierarchically but in similar fashion in AD, PD/DLB and PSP/CBD indicating that the distribution of PIN1 pathology parallels that of AD in these disorders. There was, however, only a weak correlation between hippocampal NFTs and PIN1 in PD (rs = 0.34, p = 0.028). These might represent concurrent, though independent, pathological processes. PIN1 pathology did not relate to the pattern of TDP-43 ((TAR)-DNA-binding protein) pathology in PD cases bearing that additional pathological change. PIN1 plays a pivotal role in the pathology of AD, and in other neurodegenerative disorders where additional AD pathological changes are present.