Regulation of amyloid beta-protein precursor by phosphorylation and protein interactions.
Amyloid beta-protein precursor (APP), a type I membrane protein, is cleaved by primary alpha-or beta-secretase and secondary gamma-secretase. Cleavage of APP by beta- and gamma-secretases generates amyloid beta-protein, the main constituent of the cerebrovascular amyloid that accompanies Alzheimer disease. The generation and aggregation of amyloid beta-protein in the brain are believed to be a primary cause of Alzheimer disease pathogenesis, and indeed, early onset Alzheimer disease is genetically linked to APP and also to presenilins 1 and 2, which are components of gamma-secretase. Proteolytic cleavage of APP has been investigated as a candidate target for Alzheimer disease therapy, but the mechanisms regulating APP metabolism are still unclear. APP is a type I membrane protein with a short cytoplasmic region consisting of 47 amino acids. Recent research has elucidated the significance of the cytoplasmic region in the metabolism, trafficking, and physiological function of APP. The structure and function of the APP cytoplasmic domain can be modified by phosphorylation and through interaction with cytoplasmic proteins. This minireview summarizes a large body of recent information on the regulation of APP by phosphorylation and protein interaction, along with some of the physiological functions of APP. Recent findings regarding the regulation of APP processing contribute to the development of novel drugs and/or therapies for Alzheimer disease.
Suzuki
Toshiharu
T
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan. tsuzuki@pharm.hokudai.ac.jp
Nakaya
Tadashi
T
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary
D000596:Amino Acids; D016229:Amyloid beta-Peptides