A candidate molecular mechanism for the association of an intronic polymorphism of FE65 with resistance to very late onset dementia of the Alzheimer type.
Late onset dementias of the Alzheimer type may be coupled to intrinsic aging processes. Their major pathological hallmarks are the deposition of aggregates of beta amyloid (Abeta) peptides, proteolytic products from internal portions of the Abeta precursor protein, betaPP. Susceptibility appears to be modulated by polymorphic alleles at multiple loci. Most of these putative assignments, however, have been controversial. It is therefore essential to provide evidence of a plausible biological basis for each such association. Here, we show such evidence for the case of a biallelic polymorphism of the FE65 intron 13. FE65 is an adaptor protein that tightly binds to the cytoplasmic tail of betaPP. Increasing evidence indicates that this binding plays a critical role in a signaling pathway. Our results reveal that a protective (minor) allele alters the splicing of the terminal exon by selection of an alternative acceptor site, resulting in an isoform, FE65a2, with an altered C-terminal region lacking part of a betaPP binding site. Pull down assays confirmed that the FE65a2 isoform binds to betaPP less efficiently, suggesting that an attenuated binding of FE65 with betaPP is, in part, responsible for resistance to the very late onset disease. Sequence analysis of the FE65 of mice, non-human primates and man revealed that the susceptibility allele, which codes for strong binding of the FE65 protein with betaPP, was favored by natural selection leading to our lineage. That allele may contribute to very late onset form of Alzheimer disease when we are aged.
Hu
Qubai
Q
Department of Pathology, University of Washington, Seattle, WA 98195, USA. qhu@u.washington.edu
Cool
Bethany H
BH
Wang
Baiping
B
Hearn
Mark G
MG
Martin
George M
GM
D017398:Alternative Splicing / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001483:Base Sequence; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics; D017422:Sequence Analysis, DNA
C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms