BACE1 Inhibition Increases Susceptibility to Oxidative Stress by Promoting Mitochondrial Damage

Francelin, Carolina; Mitter, Sayak K.; Qian, Qingwen; Barodia, Sandeep Kumar; Ip, Colin S.; Qi, Xiaoping; Gu, Hongmei; Quigley, Judith; Goldberg, Matthew S.; Grant, Maria B.; Boulton, Michael E.

doi:10.3390/antiox10101539

Cited by 8 publications

(2 citation statements)

References 39 publications

(53 reference statements)

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“…Several studies report a functional γ-secretase complex within mitochondria capable of generating Aβ [ 13 , 15 , 19 , 67 ]. Thus far limited studies have reported BACE1 co-localization with mitochondria in vitro [ 68 ]. Other studies have shown that Aβ is directly imported into mitochondria [ 18 ].…”

Section: The Effects Of App and App Processing On Mitochondriamentioning

confidence: 99%

Interactions between amyloid, amyloid precursor protein, and mitochondria

Wilkins

2023

Biochemical Society Transactions

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Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.

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Section: The Effects Of App and App Processing On Mitochondriamentioning

confidence: 99%

Interactions between amyloid, amyloid precursor protein, and mitochondria

Wilkins

2023

Biochemical Society Transactions

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“…In a previous study, BACE1 was pointed out to mediate the progression of Crohn’s disease by regulating cuproptosis ( 49 ). Moreover, previous studies have found that BACE1 inhibition can increase susceptibility to oxidative stress by promoting mitochondrial damage, but the exact mechanism is unclear ( 71 ). This has some similarity with the biological function of COX5A, which has been reported in previous studies to be involved in the process of aluminum-induced oxidative stress ( 72 , 73 ), promoting reduced mitochondrial biogenesis by regulating the PGC-1α signaling pathway, which coincides with the biological process of cuproptosis-regulated cell death.…”

Section: Discussionmentioning

confidence: 99%

Identification of cuproptosis-associated subtypes and signature genes for diagnosis and risk prediction of Ulcerative colitis based on machine learning

Tang

Liu

et al. 2023

Front. Immunol.

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BackgroundUlcerative colitis (UC) is a chronic and debilitating inflammatory bowel disease that impairs quality of life. Cuproptosis, a recently discovered form of cell death, has been linked to many inflammatory diseases, including UC. This study aimed to examine the biological and clinical significance of cuproptosis-related genes in UC.MethodsThree gene expression profiles of UC were obtained from the Gene Expression Omnibus (GEO) database to form the combined dataset. Differential analysis was performed based on the combined dataset to identify differentially expressed genes, which were intersected with cuproptosis-related genes to obtain differentially expressed cuproptosis-related genes (DECRGs). Machine learning was conducted based on DECRGs to identify signature genes. The prediction model of UC was established using signature genes, and the molecular subtypes related to cuproptosis of UC were identified. Functional enrichment analysis and immune infiltration analysis were used to evaluate the biological characteristics and immune infiltration landscape of signature genes and molecular subtypes.ResultsSeven signature genes (ABCB1, AQP1, BACE1, CA3, COX5A, DAPK2, and LDHD) were identified through the machine learning algorithms, and the nomogram built from these genes had excellent predictive performance. The 298 UC samples were divided into two subtypes through consensus cluster analysis. The results of the functional enrichment analysis and immune infiltration analysis revealed significant differences in gene expression patterns, biological functions, and enrichment pathways between the cuproptosis-related molecular subtypes of UC. The immune infiltration analysis also showed that the immune cell infiltration in cluster A was significantly higher than that of cluster B, and six of the characteristic genes (excluding BACE1) had higher expression levels in subtype B than in subtype A.ConclusionsThis study identified several promising signature genes and developed a nomogram with strong predictive capabilities. The identification of distinct subtypes of UC enhances our current understanding of UC’s underlying pathogenesis and provides a foundation for personalized diagnosis and treatment in the future.

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Primary Hypothyroidism and Alzheimer’s Disease: A Tale of Two

et al. 2023

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Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer’s disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aβ) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aβ and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true. Graphical Abstract

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BACE1 Inhibition Increases Susceptibility to Oxidative Stress by Promoting Mitochondrial Damage

Cited by 8 publications

References 39 publications

Interactions between amyloid, amyloid precursor protein, and mitochondria

Interactions between amyloid, amyloid precursor protein, and mitochondria

Identification of cuproptosis-associated subtypes and signature genes for diagnosis and risk prediction of Ulcerative colitis based on machine learning

Primary Hypothyroidism and Alzheimer’s Disease: A Tale of Two

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