Association between the PI*M3 allele of α1-antitrypsin and Alzheimer's disease? A preliminary report

Kowalska, Anna; Danker‐Hopfe, Heidi; Wender, M; Florczak, Jolanta; Walter, Henrik

doi:10.1007/s004390050297

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…In AD brain, AAT immunoreactivity was augmented relatively to control tissues and co‐distributed with HO‐1. In addition, the PI*M3 allele of AAT was reported in a Polish study to occur with increased frequency in patients with sporadic AD relative to the general population (Kowalska et al. 1996).…”

Section: Alzheimer Diseasementioning

confidence: 99%

Heme oxygenase‐1 and neurodegeneration: expanding frontiers of engagement

Schipper

Song

Zukor

et al. 2009

Journal of Neurochemistry

251

239

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The heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO‐2 is constitutive, abundant and fairly ubiquitous, whereas HO‐1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO‐2, the ho‐1 gene (Hmox1) is exquisitely sensitive to induction by a wide range of pro‐oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO‐1 protein is over‐expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age‐matched, cognitively intact controls and co‐localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO‐1 is markedly over‐expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up‐regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme‐derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO‐1 expression and the nature of the prevailing redox microenvironment. In ‘stressed’ astroglia, HO‐1 hyperactivity promotes mitochondrial sequestration of non‐transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging‐related neurodegenerative disorders. Glial HO‐1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.

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Section: Alzheimer Diseasementioning

confidence: 99%

Heme oxygenase‐1 and neurodegeneration: expanding frontiers of engagement

Schipper

Song

Zukor

et al. 2009

Journal of Neurochemistry

251

239

View full text Add to dashboard Cite

show abstract

“…The Alzgene website shows a single positive genetic association of AD with an α 1AT allele, from a small, unconfirmed 1996 study (62). Analysis of total α 1AT in neat undeleted plasma from individuals did not display any significant changes ( Figure 6).…”

Section: Results (1518 Words)mentioning

confidence: 97%

“…It is of interest that α1AT, which is a serpin with known associations to AD in blood (56-58), CSF(59,60) and senile plaques (61) also correlated with the APOE ε4 allele (Figure 4B), however the specific physiological role of α1AT in tissues is not well elucidated. The Alzgene website shows a single positive genetic association of AD with an α1AT allele, from a small, unconfirmed 1996 study (62). Analysis of total α1AT in neat undeleted plasma from individuals did not display any significant changes (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Discovery of plasma protein biomarkers related to Alzheimer’s disease, sex and APOE genotype

Laffoon

Doecke

Roberts

et al. 2020

Preprint

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The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimers disease. To search for biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3,400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (ZdyesTM). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. We report significant changes in variants of apolipoprotein E, haptoglobin, alpha-anti-trypsin, inter-alpha trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. Alpha-1-anti-trypsin and alpha-1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE e4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a validation study on individual samples using a targeted LC-MS/MS assay. This study indicates that a peripheral protein signature has potential to aid in the characterization of AD. We also found significant associations of protein levels with APOE genotype, indicating that differences in genotype influence the circulating abundances of proteins other than ApoE.

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“…The combination of genotyping, quantification, and phenotyping is the optimal strategy for the laboratory evaluation of a 1 -AT deficiency. The association of the PI*M3 allele of the a 1 -AT gene had been observed earlier in the pathogenesis of some disorders (McCombe et al 1985;Kowalska et al 1996). Large-scale studies and further exploration may be required in the management of diseases associated with the PI*M3 allele.…”

Section: Discussionmentioning

confidence: 93%

Analysis of the Alpha-1-Antitrypsin Deficient Alleles M3S, MZ, and ZZ by Biochemical and Molecular Methods: A Family Study

et al. 2008

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Deficiency of alpha-1-antitrypsin (alpha(1)-AT, a major protease inhibitor controlling tissue degradation) is a genetic disorder transmitted in a codominant autosomal form. It has more than 100 genetically determined variants. This study attempted to determine the degree of association between serum alpha(1)-AT levels and phenotypes and to provide a strategy for reliable laboratory evaluation of deficiencies. The study group consisted of a 38-year-old male proband with clinical features of emphysema, his first-degree relatives, and healthy controls. Family history revealed a four-generation pedigree. Genomic DNA was isolated from peripheral blood leukocytes. Alpha-1-AT levels were determined from human serum by immunonephelometry. Phenotypes were determined by isoelectric focusing of blood samples. DNA sequences of coding exons were analyzed by the amplification DNA technique and direct sequencing. Inheritance and plasma levels of the ZZ, MM, M3S, and MZ phenotypes were confirmed by the family study. In the family members with deficiencies, plasma concentrations were 22.55% +/- 5.15 (ZZ), 84.18% +/- 5.18 (M3S), and 61.06% +/- 7.15 (MZ) of the normal MM level. We found a close association between alpha(1)-AT level and genotype. A combination of genotyping, quantification, and phenotyping is the optimal strategy for the laboratory evaluation of alpha(1)-AT deficiency.

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Association between the PI*M3 allele of α1-antitrypsin and Alzheimer's disease? A preliminary report

Cited by 9 publications

References 12 publications

Heme oxygenase‐1 and neurodegeneration: expanding frontiers of engagement

Heme oxygenase‐1 and neurodegeneration: expanding frontiers of engagement

Discovery of plasma protein biomarkers related to Alzheimer’s disease, sex and APOE genotype

Analysis of the Alpha-1-Antitrypsin Deficient Alleles M3S, MZ, and ZZ by Biochemical and Molecular Methods: A Family Study

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