Year: 2017
Type: dissertation
Abstract: Amyloid precursor protein (APP) is a type-one membrane-spanning protein with a large\nextracellular N-terminal domain and a small intracellular C-terminal domain. APP first gained\ninterest due to its involvement in the pathogenesis of Alzheimer’s disease (AD). Its proteolytic\nprocessing liberates the neurotoxic amyloid-beta (Aβ) peptide that accumulates in the amyloid\nplaques, characteristic of AD. Thus, APP has been intensively studied for its amyloidogenic\nproperties with less focus on its normal cell biological roles. APP is an evolutionarily conserved\nprotein involved in biological processes including neuronal migration, synaptogenesis, synaptic\nfunction and plasticity. Still, it is unclear what role APP plays in the development of specific\nneuronal cell types in the central nervous system. The aim of this thesis was to examine the\nphysiological functions of the zebrafish Appb, a highly conserved homologue of human APP,\nduring neural development. Through a knockdown approach, we found that Appb is required for\nthe patterning and outgrowth of motor neurons in the spinal cord as well as for the synapse\nformation at the neuromuscular junction (NMJ), thus essential for the formation of normal\nlocomotor behavior. We also show the cell-specific utility of Appb in the hindbrain-specific\nMauthner cell (M-cell) development that our data indicate is mediated through a Notch1adependent\nmechanism. To confirm the function of Appb we generated an appb mutant carrying\na homozygous non-sense mutation in exon 2. Although the smaller size of mutants was similar\nto morphants, mutants appeared morphologically normal after 48 hours post-fertilization (hpf),\nsuggesting that the genetic deficit is compensated for, potentially by other App family members\nor by modifications of other genes, such as Notch. Lastly, to get a deeper insight into molecular\npathways regulated by Appb, we determined the proteomic consequence of Appb downregulation\nand provided crucial information on proteins and pathways that are differently\nexpressed when the expression of Appb is modulated. In summary, we report on an essential\nrole of Appb during neural development in the spinal cord and hindbrain and provide a link\nbetween Appb and other proteins and pathways. We believe that the zebrafish model used here\nprovided appreciable knowledge in gaining insights into APP function and that the described\nstudies above will significantly contribute to our understanding of this complex protein during\nneural development.
Author: Rakesh Kumar Banote
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2620110666