Polymorphism in genes involved in adrenergic signaling associated with Alzheimer's.
To investigate the potential involvement of adrenergic signaling in Alzheimer's disease (AD) pathogenesis, we performed genetic and functional studies of genes initiating the cascade. We chose two functional single-nucleotide polymorphisms (SNPs) in the beta1-adrenergic receptor (ADRB1) and the G protein beta3 subunit (GNB3) genes, respectively, and analyzed their allelic frequencies in a case-control sample of AD. We found that the GNB3 T allele produces a significant risk for AD in individuals homozygous for the ADRB1 C allele, suggesting that the combined effect of both polymorphisms influences AD susceptibility. Interestingly, the co-expression of GNB3 T and ADRB1 C alleles, compared with GNB3 C and ADRB1 G, produced increased cAMP levels and MAPK activation following adrenergic stimulation of transfected human cell lines. Furthermore, the co-expression of these alleles also produced increases in APP expression. These data strongly indicate that the combination of GNB3 and ADRB1 polymorphisms produces AD susceptibility by changing the cell responsiveness to adrenergic stimulation, pointing to the modulation of brain adrenergic receptors as a potential target for novel AD therapeutic strategies.
Bullido
María Jesús
MJ
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Ramos
María Carmen
MC
Ruiz-Gómez
Ana
A
Tutor
Antonio S
AS
Sastre
Isabel
I
Frank
Anna
A
Coria
Francisco
F
Gil
Pedro
P
Mayor
Federico
F
Valdivieso
Fernando
F
D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D000242:Cyclic AMP / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D044387:GTP-Binding Protein beta Subunits; D018342:Receptors, Adrenergic, beta-1; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases