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Alpha2-macroglobulin deletion polymorphism and plasma levels in late onset Alzheimer's disease
Renato Scacchi1, Maria Ruggeri, Giuseppe Gambina
1CNR Center of Evolutionary Genetics, Department of Genetics and Molecular Biology, University La Sapienza, Rome, Italy. Renato.Scacchi@uniroma1.it
Abstract:
The acute-phase "panproteinase" inhibitor alpha2-macroglobulin (alpha2M), a protein involved in inflammatory reactions, has been identified in amyloid plaques in Alzheimer's disease (AD). In addition, alpha2M is involved in AD susceptibility at the genetic level, and a deletion polymorphism at the a2M gene has been found to be associated with sporadic AD. We analyzed the deletion polymorphism and alpha2M plasma levels in 93 ultraoctuagenarian patients with late-onset sporadic AD and in controls (n=157). alpha2M allele frequencies did not differ between AD patients (alpha2M*2=0.169) and controls (alpha2M*2=0.146). The mean plasma concentrations of alpha2M were similar in patients (271.8+/-79 mg/dl) and controls (269.5+/-81.2 mg/dl). No difference was found in the alpha2M mean plasma levels associated with the three alpha2M genotypes, indicating that the deletion has no effect on alpha2M protein level. However, in AD patients alpha2M mean plasma values differed significantly according to apolipoprotein E genotypes (p=0.03), with E3/E3 homozygotes showing the highest levels. Since in a previous work E3/E3 were found to be associated with the highest plasma levels of alpha1-antichymotrypsin, another acute-phase protein, the present findings seem to support the hypothesis that inflammation may be a relevant factor in AD pathogenesis peculiar to E3/E3 subjects.
Insights
Alpha-2-macroglobulin (alpha2M), an inflammatory protein, is found in Alzheimer's disease (AD) plaques. This study found no direct link between alpha2M gene variants and AD, but identified a connection with apolipoprotein E genotypes in AD patients.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Alpha-2-macroglobulin (alpha2M), an acute-phase proteinase inhibitor, is implicated in Alzheimer's disease (AD) pathogenesis and found in AD amyloid plaques.
- A deletion polymorphism in the alpha2M gene has been previously associated with sporadic AD susceptibility.
- Understanding the role of alpha2M in AD, particularly in relation to genetic factors and plasma levels, is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To investigate the association between the alpha2M deletion polymorphism and plasma alpha2M levels in late-onset sporadic Alzheimer's disease (AD).
- To examine the relationship between alpha2M plasma concentrations and apolipoprotein E (ApoE) genotypes in AD patients.
Main Methods:
- Analysis of the alpha2M deletion polymorphism and plasma alpha2M concentrations in 93 ultraoctuagenarian AD patients and 157 controls.
- Genotyping for alpha2M and apolipoprotein E (ApoE) polymorphisms.
- Statistical analysis to compare allele frequencies, plasma levels, and genotype associations.
Main Results:
- No significant difference in alpha2M allele frequencies or mean plasma concentrations between AD patients and controls.
- The alpha2M deletion polymorphism did not influence alpha2M protein levels.
- In AD patients, alpha2M plasma levels were significantly associated with ApoE genotypes, with E3/E3 homozygotes exhibiting the highest levels.
Conclusions:
- The alpha2M deletion polymorphism is not directly associated with sporadic AD or alpha2M plasma levels in this cohort.
- The observed association between higher alpha2M levels and ApoE E3/E3 genotype in AD patients supports the hypothesis of inflammation playing a role in AD pathogenesis, particularly in this subgroup.
- These findings suggest that inflammation may be a relevant factor in AD, potentially modulated by ApoE genotype.