Alpha1-Antichymotrypsin Level in Cerebrospinal Fluid Is Closely Associated with Late Onset Alzheimer's Disease.

Harigaya, Yasuo; Shoji, Mikio; Nakamura, Tamiko; Matsubara, Etsuro; Hosoda, Kei; Hirai, Shunsaku

doi:10.2169/internalmedicine.34.481

Cited by 36 publications

(14 citation statements)

References 14 publications

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“…In vivo studies in transgenic mice have confirmed the role of ACT in promoting Aβ deposition in the brain (Mucke et al 2000;Nilsson et al 2001a). Moreover, elevated levels of ACT have been widely reported in the cerebrospinal fluid and serum of AD patients compared with controls (Harigaya et al 1995;Lieberman et al 1995;Licastro et al 1995). Our group (Kamboh et al 1995b) showed that the APOE*4-associated risk of AD is modified by the ACT signal peptide polymorphism.…”

Section: Introductionsupporting

confidence: 60%

Genetic variation in α1-antichymotrypsin and its association with Alzheimer’s disease

et al. 2002

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Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular neuritic plaques and intracellular neurofibrillary tangles in brain parenchyma. Alpha-1-antichymotrypsin (ACT) is a component of plaque cores, can bind to Abeta, and has been proposed as a possible candidate gene for AD susceptibility. The genetic association between the ACT codon -17*A allele of the signal peptide polymorphism and AD has been shown in some, but not in all studies. One hypothesis is that the ACT codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. This study was undertaken to identify new mutation(s) in the ACT gene by PCR-SSCP-sequencing and, in conjunction with known mutations, to assess their role in affecting the risk of AD. A total of seven new point mutations were observed: 5'UTR(A-->G), Asp128Asn(G-->A), Ser250Ser(C-->T), Leu301Pro(T-->C), Thr324Thr(A-->G), G-->A in intron 4, and 3'UTR C-->A. Of these, mutations at codon 250, codon 324, intron 4 and 3'UTR showed a frequency of 1% or more. Of the known mutations, Thr-17Ala(A-->G), Lys76Lys(A-->G) and Leu241Leu(G-->A) occur at a polymorphic level. The ACT codon -17*A allele was associated with increased risk of AD (OR for AA vs TT: 1.71; 95% CI: 1.16-2.53; P=0.007), especially in the presence of the APOE*4 allele (OR for AA vs TT: 2.35; 95% CI: 1.13-4.85; P=0.02). The codon 241*A allele and the codon 250*T allele were associated with protective effects against AD (OR: 0.36; 95% CI: 0.13-0.86; P=0.02) (OR:0.39; 95% CI: 0.18-0.85; P=0.02). irrespective of the APOE*4 status. The codon 324*G allele was associated with a marginal protective effect (OR:0.57; 95% CI: 0.26-1.26; P=0.17). While the codon 241*A allele was in linkage disequilibrium with the codon -17*A allele, the codon 250*T and codon 324*G alleles were non-randomly associated with the codon -17*T allele. In contrast, the codon 76*G (OR:1.34; 95% CI: 0.92-1.95; P=0.13), codon 227*G (OR:3.96; 95% CI: 0.83-18.8; P=0.08) and intron 4*G (OR:1.47; 95% CI: 0.88-2.29; P=0.15) alleles were associated with a modest risk of AD, and all were in linkage disequilibrium with the codon -17*A allele. EH-based haplotype analysis showed that certain haplotypes are associated with either higher or lower risk of AD. Our data indicate that the ACT gene harbors several potentially important variable sites, which are associated with either an increased or decreased risk of AD. The non-random combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon -17*A have been inconsistent, especially if the frequency of other ACT mutations varies between populations.

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Section: Introductionsupporting

confidence: 60%

Genetic variation in α1-antichymotrypsin and its association with Alzheimer’s disease

et al. 2002

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“…In AD, both ACT levels and genetic polymorphisms could contribute to its effects on amyloid formation, since AD patients have higher ACT levels in plasma and/or CSF (Matsubara et al, 1990;Harigaya et al, 1995;Licastro et al, 1995;Lieberman et al, 1995) and polymorphisms differentially modify AD risk (Wang et al, 2002a;Wang et al, 2002b). ACT mRNA is greatly elevated in AD (Abraham et al, 1988;Pasternack et al, 1989;Koo et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Morita

Teter

Yang

et al. 2005

Neuropsychopharmacol

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Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Ab) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

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“…The identification of such CSF spots is based on the comigration of purified proteins, immunostaining, and comparison with published 2-D maps of other tissues/body fluids. Although a relatively small number of these products have been assigned to their respective genes, several have already been suggested as diagnostic markers for Alzheimer©s disease (AD) [17], schizophrenic patients [18,19], Parkinson©s disease [19] and Creutzfeldt-Jakob disease [20]. Given that only a fraction of the silver-stainable CSF spots have been identified until now [15,16], elucidation of the remaining spots is of great interest.…”

Section: Introductionmentioning

confidence: 99%

Identification of two-dimensionally separated human cerebrospinal fluid proteins byN-terminal sequencing, matrix-assisted laser desorption/ionization — mass spectrometry, nanoliquid chromatography-electrospray ionization-time of flight-mass spectrometry, and tandem mass spectrometry

et al. 2000

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Optimal application of biological mass spectrometry (MS) in combination with two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) of human cerebrospinal fluid (CSF) can lead to the identification of new potential biological markers of neurological disorders. To this end, we analyzed a number of 2-D PAGE protein spots in a human CSF pool using spot co-localization, N-terminal sequencing, matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) and nanoliquid chromatography-electrospray ionization-time of flight-mass spectrometry (nanoLC-ESI-TOF-MS) with tandem MS switching. Our constructed CSF master contained 469 spots after image analysis and processing of 2-D gels. Upon visual inspection of our CSF master with the CSF pattern available on the ExPASy server, it was possible to locate and annotate 15 proteins. N-terminal sequence analysis and MALDI-MS peptide mass fingerprint analysis of both silver- and Coomassie Brilliant Blue (CBB) G-250-stained protein spots after in situ trypsin digest not only confirmed nine of the visually annotated spots but additionally resolved the identity of another 13 spots. Six of these proteins were not annotated on the 2-D ExPASy map: complement C3 alpha-chain (1321-1663), complement factor B, cystatin C, calgranulin A, hemoglobin beta-chain, and beta-2-microglobulin. It was clear that MALDI-MS identification from CBB G-250-stained, rather than from silver-stained, spots was more successful. In cases where no N-terminal sequence and/or no clear MALDI-MS result was available, nanoLC-ESI-TOF-MS and tandem MS automated switching was used to clarify and/or identify these protein spots by generating amino acid sequence tags. In addition, enrichment of the concentration of low-abundant proteins on 2-D PAGE was obtained by removal of albumin and immunoglobulins from the CSF pool using affinity chromatography. Subsequent analysis by 2-D PAGE of the fractionated CSF pool showed various new silver-stainable protein spots, of which four were identified by nanoLC-ESI-TOF-MS and tandem MS switching. No significant homology was found in either protein or DNA databases, indicating than these spots were unknown proteins.

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Alpha1-Antichymotrypsin Level in Cerebrospinal Fluid Is Closely Associated with Late Onset Alzheimer's Disease.

Cited by 36 publications

References 14 publications

Genetic variation in α1-antichymotrypsin and its association with Alzheimer’s disease

Genetic variation in α1-antichymotrypsin and its association with Alzheimer’s disease

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Identification of two-dimensionally separated human cerebrospinal fluid proteins byN-terminal sequencing, matrix-assisted laser desorption/ionization — mass spectrometry, nanoliquid chromatography-electrospray ionization-time of flight-mass spectrometry, and tandem mass spectrometry

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