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.
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 M(r) 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.
Mental Health and Neurodegeneration Research Group, School of Community Based Medicine, Faculty of Medical and Human Sciences, Hope Hospital, Greater Manchester Neurosciences Centre, University of Manchester, Stott Lane, Salford, M6 8HD, UK.
Ayoub
A
Dakson
Osamu
O
Yokota
Margaret
M
Esiri
Eileen H
EH
Bigio
Michael
M
Horan
Neil
N
Pendleton
Anna
A
Richardson
David
D
Neary
Julie S
JS
Snowden
Andrew
A
Robinson
Yvonne S
YS
Davidson
David M A
DM
Mann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000201:enzymology* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D004268:DNA-Binding Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
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