Human alpha2-macroglobulin: genotype-phenotype relation.
A pentanucleotide deletion polymorphism in the gene of alpha2-macrolgobulin (alpha2-M) is suggested to be associated with late-onset Alzheimer's disease (AD), though controversial results have been reported. The underlying assumption is that the intronic pentanucleotide deletion may affect the biological function and quantity of the inhibitor and thus contribute to the AD pathology. In the present study we have analyzed the distribution of the deletion polymorphism within a group of 227 healthy Caucasians. In parallel studies, we determined the plasma concentrations of total and transformed alpha2-M. A strong correlation of the total concentration of alpha2-M with age was ascertained (r(s) = -0.54, P < 0.001). However, no significant correlation between age and the genotypes (P = 0.68) was detected, and no statistically significant effect of the genotype on the concentrations of total and transformed alpha2-M was found (P = 0.49 and 0.96, respectively). A significant correlation was observed between total and transformed alpha2-M in the genotype groups Ins/Ins (r(s) = 0.56, P < 0.001) and Ins/Del (r(s) = 0.35, P < 0.004). Furthermore, in the entire data set, a significantly elevated concentration of total alpha2-M was found in females as compared to males (P = 0.003). There was a slight but nonsignificant difference in the genotype distributions between males and females (P = 0.14). To test the proposed existence of genotype-specific alterations of functional properties of alpha2-M, we isolated alpha2-M from the plasma of carriers with different genetic background and analyzed the alpha2-M subunit structure as well as the binding of the inhibitor to growth factors/cytokines, to amyloid-beta and to the receptor. The experiments failed to reveal any genotype-specific functional alterations of the alpha2-M. The absence of abnormalities in alpha2-M mRNA and protein suggests that the alpha2-M deletion polymorphism is probably not associated with functional deficiencies important in AD pathology. However, it can be speculated that the observed general age-related alpha2-M deficiency may lead to accelerated accumulation of amyloid-beta, which might be relevant to AD pathology.
Birkenmeier
G
G
Institute for Biochemistry, University of Leipzig, Liebigstrasse 16, Leipzig, Germany. birg@medizin.uni-leipzig.de
Müller
R
R
Huse
K
K
Forberg
J
J
Gläser
C
C
Hedrich
H
H
Nicklisch
S
S
Reichenbach
A
A
D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007438:Introns / Q000235:genetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011487:Protein Conformation; D012333:RNA, Messenger / Q000096:biosynthesis; D012727:Sex Characteristics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000235:genetics* / Q000502:physiology*
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D007202:Indicators and Reagents; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008233:Lymphotoxin-alpha; D010446:Peptide Fragments; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; C075222:amyloid beta-protein (1-42)