Human Molecular Genetics, 2002, Vol. 11, No. 4 465-475
© 2002 Oxford University Press
A candidate molecular mechanism for the association of an intronic polymorphism of FE65 with resistance to very late onset dementia of the Alzheimer type
1Department of Pathology and 2Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA and 3Molecular Pharmacology Research Center, New England Medical Center, Boston, MA 02111, USA
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 (Aß) peptides, proteolytic products from internal portions of the Aß precursor protein, ßPP. 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 ßPP. 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 ßPP binding site. Pull down assays confirmed that the FE65a2 isoform binds to ßPP less efficiently, suggesting that an attenuated binding of FE65 with ßPP 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 ßPP, 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.
+ To whom correspondence should be addressed. Tel: +1 206 616 4226; Fax: +1 206 685 8356; Email: qhu@u.washington.edu
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