Tyr682 in the Intracellular Domain of APP Regulates Amyloidogenic APP Processing In Vivo
Copyright policy )Tyr682 in the Intracellular Domain of APP Regulates Amyloidogenic APP Processing In Vivo
The pathogenesis of Alzheimer's disease is attributed to misfolding of Amyloid-β (Aβ) peptides. Aβ is generated during amyloidogenic processing of Aβ-precursor protein (APP). Another characteristic of the AD brain is increased phosphorylation of APP amino acid Tyr(682). Tyr(682) is part of the Y(682)ENPTY(687) motif, a docking site for interaction with cytosolic proteins that regulate APP metabolism and signaling. For example, normal Aβ generation and secretion are dependent upon Tyr(682) in vitro. However, physiological functions of Tyr(682) are unknown.To this end, we have generated an APP Y682G knock-in (KI) mouse to help dissect the role of APP Tyr(682) in vivo. We have analyzed proteolytic products from both the amyloidogenic and non-amyloidogenic processing of APP and measure a profound shift towards non-amyloidogenic processing in APP KI mice. In addition, we demonstrate the essential nature of amino acid Tyr(682) for the APP/Fe65 interaction in vivo.Together, these observations point to an essential role of APP intracellular domain for normal APP processing and function in vivo, and provide rationale for further studies into physiological functions associated with this important phosphorylation site.
- Albert Einstein College of Medicine United States
- Jackson Laboratory United States
- Feinstein Institute for Medical Research United States
- Northwell Health United States
Neurons, Amyloid, Amyloid beta-Peptides, Binding Sites, Reverse Transcriptase Polymerase Chain Reaction, Science, Q, Immunoblotting, R, Brain, Peptide Fragments, Mice, Inbred C57BL, Amyloid beta-Protein Precursor, Mice, Mutation, Medicine, Animals, Tyrosine, Gene Knock-In Techniques, Cells, Cultured, Research Article, Synaptosomes
Neurons, Amyloid, Amyloid beta-Peptides, Binding Sites, Reverse Transcriptase Polymerase Chain Reaction, Science, Q, Immunoblotting, R, Brain, Peptide Fragments, Mice, Inbred C57BL, Amyloid beta-Protein Precursor, Mice, Mutation, Medicine, Animals, Tyrosine, Gene Knock-In Techniques, Cells, Cultured, Research Article, Synaptosomes
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).59 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!