Acute Phase Reactant α1Antichymotrypsin Is Increased in Cerebrospinal Fluid and Serum of Patients with Probable Alzheimer Disease

Licastro, Federico; Parnetti, Lucilla; Morini, Maria; Davis, Lizabeth Jane; Cucinotta, Domenico; Gaiti, Alberto; Senin, Umberto

doi:10.1097/00002093-199509020-00009

Cited by 84 publications

(46 citation statements)

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“…This is even made more difficult by the lack of adequate tools to stage DLB, because the MMSE score is not a direct measure of disease severity in DLB. Nevertheless, in agreement with previously published data, we found higher levels of CSF ␣ 1 -antichymotrypsin in AD 15,44 and an association between higher plasma levels of ␣ 1 -antichymotrypsin and decline in cognitive function in individuals with AD. Importantly, this inverse relationship was restricted to ␣ 1 -antichymotrypsin because neither plasma and CSF levels of ␣ 1 -antitrypsin nor CSF levels of neuroserpin were linked to cognitive function in AD.…”

Section: Results Patient Characteristicssupporting

confidence: 93%

“…Elevated ACT in brains, 6 CSF, and serum 43,44 from AD patients have been reported earlier, and plasma ACT was found to be increased in AD patients, even without alteration of levels of other acute phase proteins such as C-reactive protein and ␣ 1 -antitrypsin. 44, 45 We found strong correlations between CSF levels of both ACT and AAT with the albumin CSF/serum ratio.…”

Section: Results Patient Characteristicssupporting

confidence: 68%

“…44, 45 We found strong correlations between CSF levels of both ACT and AAT with the albumin CSF/serum ratio. This suggests that the levels of ACT and AAT found in CSF might be derived from the periphery due to BBB dysfunction and so may be an epiphenomenon rather than central to the pathogenesis of disease.…”

Section: Results Patient Characteristicsmentioning

confidence: 63%

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Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Nielsen¹,

Minthon²,

Londos³

et al. 2007

Neurology

111

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Objective: Serine protease inhibitors (serpins), the acute phase reactants and regulators of the proteolytic processing of proteins, have been recognized as potential contributors to the pathogenesis of Alzheimer disease (AD). We measured plasma and CSF levels of serpins in controls and patients with dementia.Methods: Using rocket immunoelectrophoresis, ELISA, and Luminex xMAP technology, we analyzed plasma levels of ␣ 1 -antichymotrypsin and ␣ 1 -antitrypsin, and CSF levels of ␣ 1 -antichymotrypsin, ␣ 1 -antitrypsin, and neuroserpin along with three standard biomarkers (total tau, tau phosphorylated at threonine-181, and the A␤ 1-42 ) in patients with AD (n ϭ 258), patients with dementia with Lewy bodies (DLB; n ϭ 38), and age-matched controls (n ϭ 37). Results:The level of CSF neuroserpin was significantly higher in AD compared with controls and DLB, whereas CSF ␣ 1 -antichymotrypsin and ␣ 1 -antitrypsin were significantly higher in both AD and DLB groups than in controls. Results from logistic regression analyses demonstrate a relationship between higher CSF levels of ␣ 1 -antichymotrypsin and neuroserpin and increased predicted probability and odds ratios (ORs) of AD (OR 5.3, 95% CI 1.3 to 20.8 and OR 3.3, CI 1.3 to 8.8). Furthermore, a logistic regression model based on CSF ␣ 1 -antichymotrypsin, neuroserpin, and A␤ 1-42 enabled us to discriminate between AD patients and controls with a sensitivity of 94.7% and a specificity of 77.8%. Conclusions:Higher CSF levels of neuroserpin and ␣ 1 -antichymotrypsin were associated with the clinical diagnosis of Alzheimer disease (AD) and facilitated the diagnostic classification of AD vs controls. CSF serpin levels did not improve the diagnostic classification of AD vs dementia with Lewy bodies. Neurology ® 2007;69:1-1 GLOSSARY AAT ϭ ␣1-antitrypsin; ACT ϭ ␣1-antichymotrypsin; AD ϭ Alzheimer disease; ApoE ϭ apolipoprotein E; AUC ϭ area under the curve; BBB ϭ blood-brain barrier; COPD ϭ chronic obstructive pulmonary disease; %CV ϭ coefficients of variation percentage; DLB ϭ dementia with Lewy bodies; IL ϭ interleukin; MMSE ϭ Mini-Mental State Examination; NSAIDs ϭ nonsteroidal anti-inflammatory drugs; OR ϭ odds ratio; P-tau ϭ tau phosphorylated at threonine-181; ROC ϭ receiver operating characteristic; T-tau ϭ total tau.In addition to ␤-amyloid plaques and neurofibrillary tangles, the pathology of Alzheimer disease (AD) is characterized by excessive inflammation.1 Inflammation is driven by cytokines (particularly interleukin [IL]-1) that are released from activated microglia and astrocytes, 2 and this in turn drives the expression of IL-6 3 and inducible nitric oxide synthase. 4 Neuronal proteases that are released as part of the inflammatory response are controlled by a variety of inhibitors including members of the serine protease inhibitor (serpin) superfamily.5 These include ␣ 1 -antichymotrypsin, ␣ 1 -antitrypsin, and neuroserpin. The important role of ␣ 1 -antichymotrypsin in the pathogenesis of AD was demone-Pub ahead of print at www.neurology.org.

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Section: Results Patient Characteristicssupporting

confidence: 93%

Section: Results Patient Characteristicssupporting

confidence: 68%

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Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Nielsen¹,

Minthon²,

Londos³

et al. 2007

Neurology

111

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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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“…ACT is a major component of neuritic plaques [1] and it promotes the assembly of amyloid-ß peptide (Aß) into filaments [13] and its deposition in the brain [16,18] and it also affects cognitive impairment [17]. Compared to controls, ACT levels are elevated in the cerebrospinal fluid of AD patients [3,12] and elevated levels are also associated with AD severity [3]. Originally our group reported that the ACT/codon -17*A allele was associated with AD risk in an APOE-dependent fashion [7], however, subsequent studies showed inconsistent results [4,25].…”

Section: Introductionmentioning

confidence: 99%

Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease

Kamboh

Minster

Kenney

et al. 2006

Neurobiology of Aging

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In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer's disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the a1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon -17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p=0

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Acute Phase Reactant α1Antichymotrypsin Is Increased in Cerebrospinal Fluid and Serum of Patients with Probable Alzheimer Disease

Cited by 84 publications

References 0 publications

Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

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

Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease

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