title: Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy.
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.
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Viviana A
authors: VA
authors: Cavieres
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Alexis
authors: A
authors: González
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Vanessa C
authors: VC
authors: Muñoz
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Claudia P
authors: CP
authors: Yefi
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Hianara A
authors: HA
authors: Bustamante
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Rafael R
authors: RR
authors: Barraza
authors: Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Cheril
authors: C
authors: Tapia-Rojas
authors: Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.
authors: Carola
authors: C
authors: Otth
authors: Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: María José
authors: MJ
authors: Barrera
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.
authors: Carlos
authors: C
authors: González
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Gonzalo A
authors: GA
authors: Mardones
authors: Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro UC Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile.
authors: Nibaldo C
authors: NC
authors: Inestrosa
authors: Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors: Patricia V
authors: PV
authors: Burgos
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D015153:Blotting, Western; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D059748:Proteolysis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*
chemical_list: C502778:ATG5 protein, human; D016564:Amyloid beta-Protein Precursor; D000071187:Autophagy-Related Protein 5; C486654:EDEM1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D013729:Terpenes; D010696:Phloroglucinol; D058570:TOR Serine-Threonine Kinases; C001654:hyperforin