The impact of a novel apolipoprotein E and amyloid-β protein precursor-interacting protein on the production of amyloid-β.

Alzheimer's disease (AD) is characterized by disrupted metabolism of the amyloid-beta protein precursor (A beta PP) and deposition of a byproduct, the amyloid-beta (A beta) peptide, into plaques. AD is also genetically linked to the gene for apolipoprotein E (apoE). We have identified a novel apoE-binding protein (TMCC2) that also forms a complex with A beta PP. TMCC2 is a neuronal, predominantly ER-localized, protein that co-migrated with A beta PP during native gel electrophoresis of rat brain extracts, and co-immunoprecipitated with A beta PP from transfected human cell lysates. TMCC2 bound apoE in an isoform-specific manner in vitro and co-immunoprecipitated with apoE from cell lysates. Co-expression of apoE and TMCC2 stimulated A beta production from the "Swedish" variant of A beta PP (K595 M/N596L) by up to 1.5-fold (p < 0.05), and also from the 99-amino acid C-terminal fragment of A beta PP (A beta PP-C99) that is the direct precursor to A beta by 1.5- to 2-fold (p < 0.0005), this effect was greater with apoE4 than apoE3 (p = 0.02); both apoE3 and apoE4 stimulated a greater increase in A beta(1-42) than A beta(1-40) production from A beta PP-C99 in the presence of TMCC2. The interaction between TMCC2 and apoE may therefore contribute to disrupted A beta PP metabolism and altered A beta production, as observed in AD.