Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair.

Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-β precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following β- and γ-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription.

Astroglial tracer BU99008 detects multiple binding sites in Alzheimer's disease brain.

With reactive astrogliosis being established as one of the hallmarks of Alzheimer's disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (IBS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, IBS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains.

Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP numbering) in the APP cytoplasmic domain has been found to be phosphorylated.

Nuclear localization of amyloid-β precursor protein-binding protein Fe65 is dependent on regulated intramembrane proteolysis.

Fe65 is an adaptor protein involved in both processing and signaling of the Alzheimer-associated amyloid-β precursor protein, APP. Here, the subcellular localization was further investigated using TAP-tagged Fe65 constructs expressed in human neuroblastoma cells. Our results indicate that PTB2 rather than the WW domain is important for the nuclear localization of Fe65.

Phosphorylation of Fe65 amyloid precursor protein-binding protein in response to neuronal differentiation.

Fe65 is a brain enriched multi domain adaptor protein involved in diverse cellular functions. One of its binding partners is the amyloid-β (Aβ) precursor protein (APP), which after sequential proteolytic processing by secretases gives rise to the Alzheimer's Aβ peptide. Fe65 binds to the APP intracellular domain (AICD).