Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms

Katie Peppercorn; Torsten Kleffmann; Owen Jones; Stephanie Hughes; Warren Tate

doi:10.3389/fnins.2022.858524

Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms

Front Neurosci. 2022 May 26:16:858524. doi: 10.3389/fnins.2022.858524. eCollection 2022.

Authors

Katie Peppercorn^{1

2}, Torsten Kleffmann³, Owen Jones^{2

4}, Stephanie Hughes^{1

2}, Warren Tate^{1

2}

Affiliations

¹ Department of Biochemistry, University of Otago, Dunedin, New Zealand.
² Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
³ Division of Health Sciences, Research Infrastructure Centre, University of Otago, Dunedin, New Zealand.
⁴ Department of Psychology, University of Otago, Dunedin, New Zealand.

Abstract

Secreted amyloid precursor protein alpha (sAPPα) processed from a parent human brain protein, APP, can modulate learning and memory. It has potential for development as a therapy preventing, delaying, or even reversing Alzheimer's disease. In this study a comprehensive analysis to understand how it affects the transcriptome and proteome of the human neuron was undertaken. Human inducible pluripotent stem cell (iPSC)-derived glutamatergic neurons in culture were exposed to 1 nM sAPPα over a time course and changes in the transcriptome and proteome were identified with RNA sequencing and Sequential Window Acquisition of All THeoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS), respectively. A large subset (∼30%) of differentially expressed transcripts and proteins were functionally involved with the molecular biology of learning and memory, consistent with reported links of sAPPα to memory enhancement, as well as neurogenic, neurotrophic, and neuroprotective phenotypes in previous studies. Differentially regulated proteins included those encoded in previously identified Alzheimer's risk genes, APP processing related proteins, proteins involved in synaptogenesis, neurotransmitters, receptors, synaptic vesicle proteins, cytoskeletal proteins, proteins involved in protein and organelle trafficking, and proteins important for cell signalling, transcriptional splicing, and functions of the proteasome and lysosome. We have identified a complex set of genes affected by sAPPα, which may aid further investigation into the mechanism of how this neuroprotective protein affects memory formation and how it might be used as an Alzheimer's disease therapy.

Keywords: APP; Alzheimer’s disease; amyloid beta (A4) precursor protein; human neuron; memory; proteome; sAPPα; transcriptome.