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Alzheimer's disease (AD) is characterized by disrupted metabolism of the amyloid-β protein precursor (AβPP) and deposition of a byproduct, the amyloid-β (Aβ) 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 AβPP. TMCC2 is a neuronal, predominantly ER-localized, protein that co-migrated with AβPP during native gel electrophoresis of rat brain extracts, and co-immunoprecipitated with AβPP 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 Aβ production from the "Swedish" variant of AβPP (K595 M/N596L) by up to 1.5-fold (p < 0.05), and also from the 99-amino acid C-terminal fragment of AβPP (AβPP-C99) that is the direct precursor to Aβ 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 Aβ1-42 than Aβ1-40 production from AβPP-C99 in the presence of TMCC2. The interaction between TMCC2 and apoE may therefore contribute to disrupted AβPP metabolism and altered Aβ production, as observed in AD.

Original publication

DOI

10.3233/JAD-2011-102115

Type

Journal article

Journal

J Alzheimers Dis

Publication Date

2011

Volume

26

Pages

239 - 253

Keywords

Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Apolipoproteins E, Brain, Carrier Proteins, Humans, Neurons, Protein Binding, Rats