Melatonin Induction of APP Intracellular Domain 50 SUMOylation Alleviates AD through Enhanced Transcriptional Activation and Aβ Degradation

Yen-Chen Liu,Wei-Lun Hsu,Yun-Li Ma,Eminy H.Y Lee

doi:10.1016/j.ymthe.2020.09.003

Abstract

The amyloid precursor protein (APP) intracellular domain (AICD) is implicated in the pathogenesis of Alzheimer’s disease (AD), but post-translational modification of AICD has rarely been studied and its role in AD is unknown. In this study, we examined the role and molecular mechanism of AICD SUMOylation in the pathogenesis of AD. We found that AICD is SUMO-modified by the SUMO E3 ligase protein inhibitor of activated STAT1 (PIAS1) in the hippocampus at Lys-43 predominantly, and that knockdown of PIAS1 decreases endogenous AICD SUMOylation. AICD SUMOylation increases AICD association with its binding protein Fe65 and increases AICD nuclear translocation. Furthermore, AICD SUMOylation increases AICD association with cyclic AMP-responsive element binding protein (CREB) and p65 and their DNA binding for transcriptional activation of neprilysin (NEP) and transthyretin (TTR), two major Aβ-degrading enzymes, respectively. Consequently, AICD SUMOylation decreases the Aβ level, Aβ oligomerization, and amyloid plaque deposits. It also rescues spatial memory deficits in APP/PS1 mice. Conversely, blockade of AICD SUMOylation at Lys-43 produces the opposite effects. Melatonin is identified as an endogenous stimulus that induces AICD SUMOylation. It also decreases the Aβ level and rescues reduction of PIAS1, NEP, and TTR expression in APP/PS1 mice. In this study, we demonstrate that AICD SUMOylation functions as a novel endogenous defense mechanism to combat AD.

Highlights

The amyloid precursor protein (APP) intracellular domain (AICD) is known to regulate apoptosis, cytoskeletal dynamics, cell cycle re-entry, DNA repair, nuclear signaling, and transcriptional regulation, all of which are involved in Alzheimer’s disease (AD).[1]
AICD Is SUMO-Modified by protein inhibitor of activated STAT1 (PIAS1) Endogenously and Colocalizes with PIAS1 in the Hippocampus After showing that AICD is SUMO-modified by PIAS1 in cells, we examined whether AICD could be SUMO-modified by PIAS1 endogenously in the brain
Based on previous results showing that melatonin alleviates AD through enhanced nonamyloidogenic processing of APP and ADAM10 expression via activation of the mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinase (ERK) signaling pathway,[30] we examined whether MAPK/ERK activation mediates the effect of melatonin on PIAS1 expression

Summary

Introduction

The amyloid precursor protein (APP) intracellular domain (AICD) is known to regulate apoptosis, cytoskeletal dynamics, cell cycle re-entry, DNA repair, nuclear signaling, and transcriptional regulation, all of which are involved in Alzheimer’s disease (AD).[1] AICD is generated through both the amyloidogenic pathway and nonamyloidogenic pathway. In the amyloidogenic pathway, which mainly occurs in the endosome, AICD is generated via sequential, proteolytic cleavages of APP by b-secretase (BACE1) and g-secretase.[2] AICD interacts with other proteins, including Fe65 and Tip[60], and translocates to the nucleus for nuclear signaling and regulation of gene transcription.[3,4] In the nonamyloidogenic pathway, which mainly acts at the cell membrane, AICD is generated via sequential, proteolytic cleavages of APP by a-secretase and g-secretase.[1,5]. TTR was found to bind to Ab and protect against Ab toxicity by proteolytic cleavage of Ab and inhibition of Ab aggregation.[12,13] When g-secretase activity was inhibited in cells overexpressing APP695 (in which AICD production is presumably reduced), the TTR mRNA level was found to be decreased,[14] suggesting that AICD regulates TTR mRNA expression

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