Multi-omics analyses identify PREPL as a key regulator of protein trafficking, a pathway underlying Alzheimer's disease pathogenesis .

Current treatments for Alzheimer's disease (AD) help reduce symptoms for a limited time but do not treat the underlying pathology. To identify potential therapeutic targets for AD, an integrative network analysis was previously carried out using 364 human postmortem control, mild cognitive impairment and AD brains. This analysis identified proline endopeptidase-like protein (PREPL), an understudied protein, as a down-regulated protein in late-onset AD patients. In this study we investigate the role of PREPL. Analyses of data from human postmortem samples and PREPL knockdown (KD) cells suggest that PREPL expression modulates pathways associated with protein trafficking, synaptic activities, and lipid metabolism. Furthermore, PREPL KD impairs cell proliferation, modulates the structure of vesicles and levels of neuropeptide processing enzymes as well as secretion of neuropeptides. In addition, decrease in PREPL levels leads to changes in the levels of a number of synaptic proteins as well as changes in the levels of secreted Amyloid Beta (Ab) 42 peptide and Tau phosphorylation. Finally, we report that local decrease in PREPL levels in mouse hippocampus attenuates long-term potentiation suggesting a role in synaptic plasticity. Together, our results indicate that PREPL affects neuronal function by modulating protein trafficking and synaptic function, an important mechanism of AD pathogenesis. Significance Statement Integrative network analysis reveals PREPL to be downregulated in human sporadic late-onset Alzheimer's disease brains. Down regulation of PREPL leads to increases in Aβ secretion, Tau phosphorylation and decreases in protein trafficking and in long-term potentiation.