TUFM is involved in Alzheimer’s disease‐like pathologies that are associated with ROS

Zhong, Bi-Rou; Zhou, Gui-Feng; Li, Song; Wen, Qi-Xin; Deng, Xiao‐Juan; Ma, Yuanlin; Hu, Li-Tian; Chen, Guojun

doi:10.1096/fj.202002461r

Cited by 18 publications

(11 citation statements)

References 62 publications

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“…As shown in Figure 2D, although LY2886721 and GI254023X together significantly increased the basal protein level of APP, they did not prevent the reduction of APP protein in HEK‐APP cells transiently transfected with AP2S1 siRNA, indicating that AP2S1‐mediated regulation of APP protein level was unrelated to the enzymatic activity of BACE1 and ADAM10. Moreover, the decreased levels of both the immature and mature forms of APP might be suggestive of an altered protein synthesis mechanism, we thus assessed the effect of AP2S1 in cells treated with protein synthesis inhibitor cycloheximide (CHX, 5 μM for 6 h) 38 . As shown in Figure 2E, although CHX significantly reduced the basal protein level of APP, it did not prevent AP2S1 KD‐induced reduction of APP.…”

Section: Resultsmentioning

confidence: 99%

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

Wen

Luo

Xie

et al. 2022

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AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic β-amyloid peptide (Aβ). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aβ in cells stably expressing human full-length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation.Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9-positive late endosomes (LE) to LAMP1-positive lysosomes, which was paralleled by the enhanced LE-lysosome fusion. In support, silencing of vacuolar protein sorting-associated protein 41 (VPS41) that is implicated in LE-lyso fusion prevented AP2S1-mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV-mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aβ, with the concomitant APP translocalization, LE-lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE-lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.

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Section: Resultsmentioning

confidence: 99%

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

Wen

Luo

Xie

et al. 2022

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“…Collectively, TUFM protein levels were decreased in APP/PS1 mice. Taken together these results pointed at TUFM involvement in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role [ 130 ].…”

Section: Focus On Experimental Models Of Ad and Potential Antioxidant Therapeutic Targetsmentioning

confidence: 91%

“…Mitochondrial Tu translation elongation factor (TUFM or EF-Tu) can maintain mitochondrial respiratory chain activity and protect cell against OS. TUFM protein level is decreased in the hippocampus and cortex in the aged APP/PS1 mice [ 130 ]. Further, cellular ROS levels were affected by TUFM expression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation is counteracted by the treatment with TEMPO, a potent antioxidant drug.…”

Section: Focus On Experimental Models Of Ad and Potential Antioxidant Therapeutic Targetsmentioning

confidence: 99%

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

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“…Ultimately, the accelerated revascularization stimulated the regeneration of the dental pulp. Furthermore, compared with the control group, the DPSC-ABs-treated group showed thickened dentin and elongated root [ 62 ].…”

Section: Biological Properties and Functions Of Mesenchymal Stem Cell...mentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Apoptotic Bodies: Biological Functions and Therapeutic Potential

Tang

Luo

Zhang

et al. 2022

Cells

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Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells with self-renewal ability and multipotency of osteogenic, chondrogenic, and adipogenic differentiation. MSCs have appeared as a promising approach for tissue regeneration and immune therapies, which are attributable not only to their differentiation into the desired cells but also to their paracrine secretion. MSC-sourced secretome consists of soluble components including growth factors, chemokines, cytokines, and encapsulated extracellular vesicles (EVs). Apoptotic bodies (ABs) are large EVs (diameter 500𠀓2000 nm) harboring a variety of cellular components including microRNA, mRNA, DNA, protein, and lipids related to the characteristics of the originating cell, which are generated during apoptosis. The released ABs as well as the genetic information they carry are engulfed by target cells such as macrophages, dendritic cells, epithelial cells, and fibroblasts, and subsequently internalized and degraded in the lysosomes, suggesting their ability to facilitate intercellular communication. In this review, we discuss the current understanding of the biological functions and therapeutic potential of MSC-derived ABs, including immunomodulation, tissue regeneration, regulation of inflammatory response, and drug delivery system.

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TUFM is involved in Alzheimer’s disease‐like pathologies that are associated with ROS

Cited by 18 publications

References 62 publications

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Mesenchymal Stem Cell-Derived Apoptotic Bodies: Biological Functions and Therapeutic Potential

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