Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy.

Viviana A Cavieres,Rafael R Barraza,María José Barrera,Vanessa C Muñoz,Claudia P Yefi,Carola Otth,Carlos González,Gonzalo A Mardones,Alexis González,Cheril Tapia-Rojas,Patricia V Burgos,Hianara A Bustamante,Nibaldo C Inestrosa

doi:10.1371/journal.pone.0136313

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706) prevents accumulation of Aβ species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD). Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP), resulting in the accumulation of immature APP (iAPP) in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aβ production in vivo.

Highlights

Alzheimer's disease (AD) is the most common neurodegenerative disorder among older adults, and is characterized by the progressive deterioration of cognitive functions and the cerebral accumulation of both extracellular amyloid plaques and neurofibrillary tangles in hippocampal regions of the brain [1]
Misfolded glycoproteins that fail to attain their correct conformation in the endoplasmic reticulum (ER) are recruited by EDEM1 from the Calnexin/Calreticulin folding cycle, and are retro-translocated for cytosolic degradation via ER-associated degradation (ERAD) [21,22]
We present evidence suggesting that IDN5706, a synthetic derivative of the chemical compound hyperforin of the St John's Wort plant, modulates EDEM1 levels, a key component of the endoplasmic-reticulum-associated degradation (ERAD) pathway and, at the same time, enhances early degradation of immature APP (iAPP) via Atg5-dependent autophagy

Summary

Introduction

Alzheimer's disease (AD) is the most common neurodegenerative disorder among older adults, and is characterized by the progressive deterioration of cognitive functions and the cerebral accumulation of both extracellular amyloid plaques and neurofibrillary tangles in hippocampal regions of the brain [1]. Amyloid plaques are highly enriched in aggregated amyloid-β (Aβ) peptide species, derived from the sequential proteolysis of the amyloid precursor protein (APP) by the β-site APP cleaving enzyme 1 (β-secretase) [2] and the γ-secretase complex [3]. Despite significant progress in the understanding of AD, further research is needed to elucidate the mechanisms underlying the accumulation of Aβ peptide that leads to early-onset AD. Tetrahydrohyperforin (IDN5706), a semi synthetic derivative of hyperforin, the active molecule in the St John's Wort plant (Hypericum perforatum), as well as the natural compound hyperforin itself [4,5], have been shown to prevent neuropathological changes in a mouse model of AD [6,7]. IDN5706 is a potent inhibitor of γsecretase-mediated cleavage of the amiloydogenic carboxy-terminal fragment-β (CTFβ) [7]

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Results

Conclusion