The Significance of Pin1 in the Development of Alzheimer's Disease

Wang, Haihui; Simon, B.; Bennett, David A.; Schneider, Julie A.; Malter, James S.; Wang, Deng Shun

doi:10.3233/jad-2007-11105

Cited by 39 publications

(30 citation statements)

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“…Following death, all available clinical data were reviewed by an expert neurologist blinded to neuropathology and a clinical diagnosis was rendered. MTG and MFG samples were examined from 29 NI, 28 MCI, and 23 AD cases as previously diagnosed [8]. Caudate and cerebellar samples were examined from 12 NI, 10 MCI, and 11 AD cases.…”

Section: Methodsmentioning

confidence: 99%

Altered NEP2 Expression and Activity in Mild Cognitive Impairment and Alzheimer's Disease

Huang

Hafez

James

et al. 2012

JAD

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Neprilysin-2 (NEP2), a close homolog of neprilysin (NEP), degrades amyloid-β (Aβ) and serves an important role in clearing Aβ in vivo. We measured NEP2 and NEP mRNA levels from non-impaired (NI), mild cognitive impaired (MCI), and clinical Alzheimer’s disease (AD) subjects in the mid-temporal gyrus, mid-frontal gyrus, caudate, and cerebellum. NEP2 activity levels were also determined. Our results indicate that NEP2 and NEP mRNA expression is altered in MCI subjects relative to NI subjects in AD-susceptible regions. NEP2 enzymatic activity was lowered in association with MCI and AD and was positively associated with level of cognitive function, independent of diagnostic category. Our finding that NEP2 expression and activity are altered in MCI is significant as these changes may potentially serve as preclinical markers for AD and reduced NEP2 activity may be associated with the development of AD.

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Section: Methodsmentioning

confidence: 99%

Altered NEP2 Expression and Activity in Mild Cognitive Impairment and Alzheimer's Disease

Huang

Hafez

James

et al. 2012

JAD

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“…The immunoprecipitated proteins were eluted by adding ImmunoPure® Elution Buffer and then analyzed by Western blotting with anti-HNE and anti-NEP polyclonal antibodies. The density of the NEP and HNE blotting bands were quantified by ImageJ software (1.37v, Wayne Rasband, National Institutes of Health,) as described [56, 57]. The ratio of HNE/NEP was calculated from the same sample to assess the relative level of HNE-NEP adducts.…”

Section: Methodsmentioning

confidence: 99%

N-Acetylcysteine Prevents 4-Hydroxynonenal- and Amyloid-β-Induced Modification and Inactivation of Neprilysin in SH-SY5Y Cells

Wang

Malter

Wang

2010

JAD

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As one of the dominant amyloid-β peptide (Aβ) proteases, neprilysin (NEP) plays a crucial role in maintaining a physiologic balance between Aβ production and catabolism. We have previously shown that NEP is modified by 4-hydroxynonenal (HNE) adducts, resulting in decreased activity in the brain of AD patients and cultured cells. In order to determine whether antioxidants can rescue NEP, SH-SY5Y cells were treated with HNE or Aβ, together with N-acetylcysteine for 24 hours, prior to analysis of NEP protein levels, activity, and oxidative modifications. Intracellular NEP developed HNE adducts after 24 hours of HNE or Aβ treatment as determined by immunoprecipitation, immunoblotting, and double immunofluorescence staining. N-acetylcysteine at 10 to 100 μM alleviated HNE adduction after HNE or Aβ treatment. In keeping with previous reports, HNE-modified NEP showed decreased catalytic activity. The present study demonstrates that antioxidants can be used to spare NEP from oxidative modification, suggesting a potential mechanism underlying the neuroprotective effects of antioxidants in aging or Alzheimer’s disease.

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“…First, Wang et al [21] suggested that reduced Pin1 activity in the frontal cortex of patients with mild cognitive impairment contributes to the initial accumulation of hyperphosphorylated tau and is then followed, in a more advanced stage of the disease, by a compensatory upregulation of the Pin1 gene that counteracts A ␤ plaque formation. Consistently with this hypothesis, in PBMCs of subjects with overt disease, we observed a significant increase in Pin1 gene expression together with a significant decrease in gene promoter methylation.…”

Section: Discussionmentioning

confidence: 99%

Pin1 Contribution to Alzheimer’s Disease: Transcriptional and Epigenetic Mechanisms in Patients with Late-Onset Alzheimer’s Disease

Arosio¹,

Bulbarelli²,

Candia³

et al. 2012

Neurodegener Dis

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Background: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer’s disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. Objective: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). Methods: Gene and protein expression, promoter methylation, Ser¹⁶ phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. Results: In LOAD subjects, there was a statistically significant reduction in Ser¹⁶ phosphorylation (–30%; p = 0.041) and promoter methylation (–8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). Conclusion: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.

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The Significance of Pin1 in the Development of Alzheimer's Disease

Cited by 39 publications

References 0 publications

Altered NEP2 Expression and Activity in Mild Cognitive Impairment and Alzheimer's Disease

Altered NEP2 Expression and Activity in Mild Cognitive Impairment and Alzheimer's Disease

N-Acetylcysteine Prevents 4-Hydroxynonenal- and Amyloid-β-Induced Modification and Inactivation of Neprilysin in SH-SY5Y Cells

Pin1 Contribution to Alzheimer’s Disease: Transcriptional and Epigenetic Mechanisms in Patients with Late-Onset Alzheimer’s Disease

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