REVIEW: Pin1 in Alzheimer's disease

Abstract

Proteolytic processing and phosphorylation of amyloid precursor protein (APP), and hyperphosphorylation of tau protein, have been shown to be increased in Alzheimer's disease (AD) brains, leading to increased production of b-amyloid (Ab) peptides and neurofibrillary tangles, respectively. These observations suggest that phosphorylation events are critical to the understanding of the pathogenesis and treatment of this devastating disease. Pin-1, one of the peptidyl-prolyl isomerases (PPIase), catalyzes the isomerization of the peptide bond between pSer/Thr-Pro in proteins, thereby regulating their biological functions which include protein assembly, folding, intracellular transport, intracellular signaling, transcription, cell cycle progression and apoptosis. A number of previous studies have shown that Pin1 is co-localized with phosphorylated tau in AD brain, and shows an inverse relationship to the expression of tau. Pin1 protects neurons under in vitro conditions. Moreover, recent studies demonstrate that APP is a target for Pin1 and thus, in Ab production. Furthermore, Pin1 was found to be oxidatively modified and to have reduced activity in the hippocampus in mild cognitive impairment (MCI) and AD. Because of the diverse functions of Pin1, and the discovery that this protein is one of the oxidized proteins common to both MCI and AD brain, the question arises as to whether Pin1 is one of the driving forces for the initiation or progression of AD pathogenesis, finally leading to neurodegeneration and neuronal apoptosis. In the present review, we discuss the role of Pin1 with respect to Alzheimer's disease.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…In AD brain, Pin1 is found to be colocalized with phosphorylated tau and also shows an inverse relationship to the expression of tau in AD brains (196,316). Further, Pin1 was also identified by redox proteomics as oxidatively modified protein in AD hippocampus (65,363). Oxidation and decreased levels and activity of this protein could favor the formation of NFTs, SP, and subsequent synapse or cell loss due to cell arrest (20).…”

“…After this study, a number of other targets of oxidation have been reported from our laboratory in different brain regions, and these studies also showed that oxidatively modified proteins are prone to inactivation (80,368,369). Brain from subjects with amnestic mild cognitive impairment (MCI) showed increased levels of PCO compared with the age-matched controls (10,65,76,222). Further, global OS measurements revealed significantly higher levels of PCO in the MCI IPL relative to preclinical AD (PCAD) (and controls), despite equal levels of neuropathology (10).…”

“…Pin1 is a regulatory protein that recognizes phosphorylated Ser-Pro or phosphorylated Thr-Pro motifs in target proteins. After binding to this motif on the target protein by the WW domain of Pin1, the PPIase active site domain of Pin1 alters the sterochemistry of the Pro residue of the target protein from cis to trans and vice versa, thereby regulating the activity of the target protein (65,339). Pin1 plays an important role in the cell growth and is required for proper progression 1628 BUTTERFIELD ET AL.…”

Structure and function of the human parvulins Pin1 and Par14/17

“…Cys 113 was found to be sensitive to oxidation by increased reactive oxygen species found in AD patients thereby losing the protein's catalytic activity upon tau protein (Sultana et al, 2006;Chen et al, 2015;Innes et al, 2015). In summary, all events leading to a down-regulation of Pin1 in brain boost the likelihood of AD onset (Butterfield et al, 2006). Despite Pin1 up-regulation processes delay AD onset (Ma et al, 2012) they may increase the risk and early onset of frontotemporal atrophy (Lim et al, 2008;Ferri et al, 2016).…”

“…Cis p-tau was found to be a precursor of tau pathology and an early driver of neurodegeneration in AD. Pin1 protects against tau-aggregation by isomerizing p-tau and (Butterfield et al, 2006) by regulating tau dephosphorylation (Lu et al, 1999a. Pin1 also slows down the amyloidogenic Aβ production from amyloid precursor protein (APP) (Pastorino et al, 2006).…”