FE65 is predominantly expressed in brain and is especially rich in the regions with the highest densities of neurons. The FE65 protein binds to an intracellular domain of the beta-amyloid precursor protein (betaPP) and may modulate the production of beta-amyloid peptide (AP). One of FE65 exons, a mini-exon (exon 9, 6 bp), is alternatively spliced, giving rise to two isoforms varying only in 6 base pairs. We quantitated the two isoforms by a sensitive reverse transcription-competitive polymerase chain reaction technique, and characterized their expressions in various tissues and cell cultures, and the kinetics of expression of the two isoforms in P19 embryonal carcinoma cell lines during neuronal differentiation. Our results show that the exon 9-inclusive (E9) form, the more abundant form in brain, was exclusively expressed in neurons, while the exon 9-exclusive (DeltaE9) form was widely expressed in all non-neuronal cells, but was not expressed in differentiated neurons. When P19 cells were differentiated to neurons, expression of FE65 was significantly up regulated ( approximately 30-fold) and the splicing pattern of the FE65 pre-mRNA was switched from the DeltaE9 pattern to the E9 form. Based upon their distinctive expression patterns, these two isoforms may serve as neuronal and non-neuronal markers, and determination of their ratios may have applications in neuropathological diagnosis.
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.
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