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O2–04–01: Combined amyloid and tau–pathology in APPV717I X taup301L double transgenic mice: Increased survival correlates with less hindbrain pathology, despite dramatic forebrain tauopathy
Author(s) -
Muyllaert David,
Terwel Dick,
Dewachter Ilse,
Borghgraef Peter,
Van Leuven Fred
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.129
Subject(s) - tauopathy , genetically modified mouse , forebrain , pathology , biology , senile plaques , transgene , amyloid precursor protein , tau protein , hippocampus , neuroscience , neurodegeneration , alzheimer's disease , medicine , central nervous system , genetics , disease , gene
interacting protein(s). Our objectives are to identify such proteins by proteomic analysis and to elucidate the regulation mechanisms of BACE1 activity. Methods: Human neuroblastoma SH-SY5Y cells overexpressing BACE1 with a C-terminal tag were used as a source material. Possible BACE1-interacting proteins were separated by affinity purification and further analyzed by mass spectrometry. Protein-protein interaction was analyzed by co-immunoprecipitation. A levels were measured using sandwich ELISA kits. Results: We identified Nogo-B (reticulon 4-B; RTN4-B) as a BACE1-binding protein. Co-immunoprecipitaion experiments confirmed a physical association between BACE1 and Nogo-B, Nogo-C (RTN4-C), and their homologue reticulon 3 (RTN3). Overexpression of these RTN proteins resulted in a 30-50% reduction in the secretion of both A 40 and A 42 from human embryonic kidney 293 cells expressing Swedish mutant amyloid precursor protein (APP). These proteins, however, did not influence A secretion from cells expressing the APP Cterminal fragment. In addition, immunohistochemical analysis showed that RTN3 is predominantly expressed by pyramidal neurons in the mouse cerebral cortex. Conclusions: These data collectively indicate that NogoB/C and RTN3 can negatively modulate BACE1 cleavage of APP, suggesting that they play important roles in the regulation of A production in the brain.