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Biochemistry. 2015 May 5;54(17):2777-84. doi: 10.1021/acs.biochem.5b00217. Epub 2015 Apr 23.

Impact of amyloid precursor protein hydrophilic transmembrane residues on amyloid-beta generation.

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†Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, H3G 1Y6 Montréal, Canada.
‡Institut für Chemie und Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
∥Integrated Program in Neuroscience, McGill University, Montréal, Canada.
§Institut für Medizinische Physik und Biophysik, Charité, Charitéplatz 1, 10117 Berlin, Germany.


Amyloid-β (Aβ) peptides are likely the molecular cause of neurodegeneration observed in Alzheimer's disease. In the brain, Aβ42 and Aβ40 are toxic and the most important proteolytic fragments generated through sequential processing of the amyloid precursor protein (APP) by β- and γ-secretases. Impeding the generation of Aβ42 and Aβ40 is thus considered as a promising strategy to prevent Alzheimer's disease. We therefore wanted to determine key parameters of the APP transmembrane sequence enabling production of these Aβ species. Here we show that the hydrophilicity of amino acid residues G33, T43, and T48 critically determines the generation of Aβ42 and Aβ40 peptides (amino acid numbering according to Aβ nomenclature starting with aspartic acid 1). First, we performed a comprehensive mutational analysis of glycine residue G33 positioned within the N-terminal half of the APP transmembrane sequence by exchanging it against the 19 other amino acids. We found that hydrophilicity of the residue at position 33 positively correlated with Aβ42 and Aβ40 generation. Second, we analyzed two threonine residues at positions T43 and T48 in the C-terminal half of the APP-transmembrane sequence. Replacement of single threonine residues by hydrophobic valines inversely affected Aβ42 and Aβ40 generation. We observed that threonine mutants affected the initial γ-secretase cut, which is associated with levels of Aβ42 or Aβ40. Overall, hydrophilic residues of the APP transmembrane sequence decide on the exact initial γ-cut and the amounts of Aβ42 and Aβ40.

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