Trientine Reduces BACE1 Activity and Mitigates Amyloidosisviathe AGE/RAGE/NF-κB Pathway in a Transgenic Mouse Model of Alzheimer's Disease

Autor: Jing-Wei Xie, Ye Xu, Bao-Lu Zhao, Zhan-You Wang, Chun-Yan Wang, Jian-Hui Cai, Tao Wang, Li An, Xu Wang
Rok vydání: 2013
Předmět:
Glycation End Products
Advanced
Physiology
Receptor for Advanced Glycation End Products
Clinical Biochemistry
Pharmacology
medicine.disease_cause
Trientine
Biochemistry
Mice
chemistry.chemical_compound
Superoxide Dismutase-1
Glycation
Malondialdehyde
Aspartic Acid Endopeptidases
Receptors
Immunologic
Chelating Agents
General Environmental Science
Cerebral Cortex
biology
Chemistry
NF-kappa B
Ceruloplasmin
Amyloidosis
Original Research Communications
Female
Signal transduction
Signal Transduction
Genetically modified mouse
medicine.medical_specialty
Down-Regulation
Mice
Transgenic
Downregulation and upregulation
Alzheimer Disease
Cell Line
Tumor
Internal medicine
mental disorders
medicine
Animals
Humans
Molecular Biology
Superoxide Dismutase
NF-κB
Cell Biology
NFKB1
Mice
Inbred C57BL
Endocrinology
biology.protein
General Earth and Planetary Sciences
Amyloid Precursor Protein Secretases
Amyloid precursor protein secretase
Copper
Oxidative stress
Zdroj: Antioxidants & Redox Signaling. 19:2024-2039
ISSN: 1557-7716
1523-0864
DOI: 10.1089/ars.2012.5158
Popis: Aims: There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1) double transgenic (Tg) AD model mice. Results: We observed that Trien reduced the level of advanced glycation end products (AGEs), and decreased Aβ deposition and synapse loss in brain of APP/PS1 mice. Importantly, we found that Trien blocked the receptor for AGEs (RAGE), downregulated β-site APP cleaving enzyme 1 (BACE1), inhibited amyloidogenic APP cleavage, and subsequently reduced Aβ levels. In vitro, in SH-SY5Y cells overexpressing Swedish mutant APP, Trien-mediated downregulation of BACE1 occurred via inhibition of the NF-κB signaling pathway. Innovation: In this study, we demonstrated for the first time that Trien inhibited amyloidogenic pathway including targeting the downregulation of RAGE and NF-κB. Conclusion: Trien might mitigate amyloidosis in AD by inhibiting the RAGE/NF-κB/BACE1 pathway. Our study demonstrates that Trien may be a viable therapeutic strategy for the intervention and treatment of AD and other AD-like pathologies. Antioxid. Redox Signal. 19, 2024–2039.
Databáze: OpenAIRE
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