Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer's disease. (September 2017)

• Record Type: Journal Article
• Authors: Bukhari, Hassan; Glotzbach, Annika; Kolbe, Katharina; Leonhardt, Gregor; Loosse, Christina; Müller, Thorsten
• Is Part Of: Progress in neurobiology. Volume 156(2017:Sep.)
• Page Start: 189
• Page End: 213
• Publication Date: 2017-09
• Subjects: Aβ amyloid β -- AD Alzheimer's disease -- AFT complexes APP/AICD-FE65-TIP60 complexes -- AICD APP intracellular domain -- APLP1, 2 amyloid precursor like protein 1, 2 -- APP amyloid precursor protein -- ChIP chromatin immuneprecipitation -- CTF C-terminal fragment -- DSB double strand break -- DTT Dithiothreitol -- EOFAD early onset familiar AD -- FE65L1 FE65 like 1 -- HAT histone acetyltransferase -- H2O2 hydrogen peroxide -- IUD intrinsically unstructured domain -- KD knock-down -- KO knock-out -- NaCl sodium chloride -- NFT neurofibrillary tangles -- NH4Cl ammonium chloride -- NLS nuclear localization sequence -- NMR nuclear magnetic resonance -- miRNAs micro RNAs -- pT phosphorylated T -- PTB phosphotyrosine binding -- RIP regulated intermembrane proteolysis -- sAPPβ soluble APP -- swAPP Swedish APP -- TGN trans-Golgi network -- TM transmembrane -- wt wildtype; Alzheimer's disease -- APP intracellular domain (AICD) -- APP phosphorylation -- AICD nuclear signaling -- Nuclear spheres -- FE65; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2017.05.005
• Languages: English
• ISSNs: 0301-0082

Abstract

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disease with tens of millions of people affected worldwide. The pathogenesis is still poorly understood and various therapeutical approaches targeting the amyloid β (Aβ) peptide, a product of the amyloidogenic cleavage of the amyloid precursor protein (APP), failed. Moreover, a couple of studies critically questioned the relevance of Aβ in the pathogenesis of AD. Thus, new ideas need to be studied and one highly interesting hypothesis is the APP mediated signal transduction to the nucleus. As a consequence nuclear –potentially toxic- structures emerge, which were recently found to a high extent in human AD tissue and thus, may contribute to neurodegeneration. Relevant for the signaling machinery are modifications at the very C-terminal end of the precursor protein, the APP intracellular domain (AICD). In this review we update the knowledge on mechanisms on AICD referring to our 2008 article: The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics—Relevance for Alzheimer's disease (T. Muller, et al., 2008). We summarize how AICD is generated and degraded, we describe its intramolecular motifs, translational modifications, and how those as well as APP dimerization influence AICD generation and function. Moreover, we resume the AICD interactome and elucidate AICDs involvement in nuclear signaling, transcriptional regulation, cell death, DNA repair and cell cycle re-entry and we give insights in its physiological function. Results are summarized in the comprehensive poster "The world of AICD".