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Ageing, Neurodegeneration and Alzheimer's Disease
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Richard J. Elsworthy, Sarah Aldred
Oxidation of proteins involved in Aβ clearance and degradation is evident in people with AD, suggesting oxidative distress may indeed be involved in early AD pathogenesis (Owen et al., 2010; Wang et al., 2003). However, the interaction between oxidative distress and Aβ accumulation is bidirectional in that oligomeric Aβ can trigger the propagation of oxidising cascades. This is perhaps most evident in lipid membranes. As previously mentioned, Aβ1–42 can readily form hydrophobic oligomers in lipid-rich membrane domains (Zheng et al., 2017) with the ability to insert and disrupt membrane structure. Aβ oligomers can then oxidise membrane lipids forming highly reactive electrophilic aldehydes, such as 4-hydroxynonenal (HNE), malondialdehyde and acrolein. HNE has been of particular interest, as elevated levels are associated with AD pathology (Benseny-Cases et al., 2014; Markesbery and Lovell, 1998; Scheff et al., 2016). Not only this, HNE-modified proteins are also elevated in AD (Butterfield et al., 2006; Perluigi et al., 2009). The addition of protein adducts such as HNE or a carbonyl group to membrane, cytosolic and mitochondrial proteins can subsequently result in protein dysfunction and may be critical in the progression of AD (Butterfield, 2020). Most notably, HNE bound to the low-density lipoprotein receptor-related protein 1 (LRP1) can significantly impair Aβ clearance. Consequently, the accumulation of Aβ in tandem with its oxidising potential may further oxidise LRP1, suggesting Aβ may impair its own clearance (Owen et al., 2010).
Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Tasnuva Sarowar, Md. Hafiz Uddin
Under normal physiological condition, abeta is degraded and cleared easily. But in case of AD patients, the abeta peptides form aggregates and become resistant to degradation. For example, abeta can be cleared by lipoprotein receptor-related protein (LRP1) (Donahue et al. 2006), which efflux abeta from the brain to CSF. Abeta can oxidize LRP1 and inhibit its own clearance (Owen et al. 2010). Abeta is also known to trigger NMDA-mediated Ca2+ influx and stress-related signaling pathways (Danysz and Parsons 2012), which gives rise to ROS. The pathological abeta can exert cytotoxicity via various pathways, including but not limited to oxidative stress, inflammation, and apoptosis (Finder and Glockshuber 2007).
Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
Low-density lipoprotein receptor-related protein 1 (LRP1): Aβ is produced from the APP, both in the brain and in peripheral tissues. In plasma, a soluble form of LRP1 (sLRP1) is the major transport protein for peripheral Aβ. sLRP1 maintains a plasma “sink” activity for Aβ through binding of peripheral amyloid-β which in turn inhibits reentry of free plasma amyloid-β into the brain. LRP1 in the liver mediates systemic clearance of amyloid-β. LRP1 at the BBB and contributes to the clearance of amyloid-β from the brain. LRP1 mediates rapid efflux of a free, unbound form of amyloid-β and of amyloid-β bound to apolipoprotein E2 (APOE2), APOE3 or α2-macroglobulin from the brain's ISF into the blood, and APOE4 inhibits such transport. In AD, LRP1 expression at the BBB is reduced and amyloid-β binding to circulating sLRP1 is compromised by oxidation (Sagare et al. 2012). Moreover, amyloid-β damages its own LRP1-mediated transport by oxidating LRP1 (Owen et al. 2010). Defects in LRP-1-mediated Aβ clearance from the brain are thought be triggered by systemic inflammation by lipopolysaccharide, leading to increased brain accumulation of amyloid-β (Bulbarelli et al. 2012, Erickson et al. 2012).
Alpha-momorcharin regulates cytokine expression and induces apoptosis in monocytes
Published in Immunopharmacology and Immunotoxicology, 2019
Nianhua Deng, Yun Sun, Mengling Liu, Qianchuan He, Ling Wang, Yu Zhang, Wenkui Sun, Ning Lei, Yang Liu, Yingxia Luo, Fubing Shen
In in vivo, high doses of α-MMC can cause a decrease in the number of monocytes, and in vitro experiments have confirmed that the mechanism of action is α-MMC-induced apoptosis, as shown in Figure 6. The results of in vitro experiments also showed that at the same dose, α-MMC-induced apoptosis of THP-1 monocytes; this apoptosis was much higher than that of the B lymphocyte strain WIL2-S and the T lymphocyte strain Jurkat. Additionally, at a cytotoxicity-free dose, α-MMC regulated cytokine expression in THP-1 cells but had no effect on WIL2-S and Jurkat cells. The selective action of α-MMC on monocytes may be related to the distribution density of the specific cell membrane receptor for α-MMC. In previous experiments, we confirmed that the specific receptor for α-MMC is low density lipoprotein receptor-related protein 1(LRP1) [22]. The literature indicates a significant difference in the distribution of LRP1 receptors on immune cells [23]. The distribution density of LRP1 on the surface of monocytes is 12618 ± 3766/cell, while that of lymphocytes is only 41 ± 44/cell. The binding of α-MMC to the cell membrane LRP1 receptor and its introduction into cells is a key to its biological effects. The receptor-mediated immunosuppressive mechanism of monocytes has been confirmed by us, and the results of the study will be published in another paper [24]. Therefore, we envisage that by using the LRP1 receptor blocker or knocking out the receptor binding site of α-MMC to reduce the immunosuppressive side effects of α-MMC.
Butyrate-Induced In Vitro Colonocyte Differentiation Network Model Identifies ITGB1, SYK, CDKN2A, CHAF1A, and LRP1 as the Prognostic Markers for Colorectal Cancer Recurrence
Published in Nutrition and Cancer, 2019
Nirmalya Dasgupta, Bhupesh Kumar Thakur, Abhijit Chakraborty, Santasabuj Das
LRP1 (also known as CD91) is a widely-expressed multifunctional endocytic and cell-signaling receptor that binds to multiple extracellular ligands, including several heat shock proteins (HSPs). Emerging evidence suggests the involvement of LRP1 in tumor development and progression in several cancers, while its expression was correlated with invasiveness, tumor stage, and clinical outcome (60). We found that induced expression of LRP1 was associated with poor prognosis of CRC in clinical samples and increased the risk of recurrence by 20–200% (Table 4), in addition to stage-wise increment of LRP1 expression in TCGA-COAD dataset. Decreased expression of LRP1 in APC and p53 mutated patient samples further justified the use of in vitro colonocyte differentiation model.
New insight into brain disease therapy: nanomedicines-crossing blood–brain barrier and extracellular space for drug delivery
Published in Expert Opinion on Drug Delivery, 2022
Ziqi Gu, Haishu Chen, Han Zhao, Wanting Yang, Yilan Song, Xiang Li, Yang Wang, Dan Du, Haikang Liao, Wenhao Pan, Xi Li, Yajuan Gao, Hongbin Han, Zhiqian Tong
The low-density lipoprotein receptor (LDLR) superfamily contains low-density lipoprotein receptor-related protein 1 (LRP1), LRP1B, LRP3, LRP4, LRP5, and LRP6 etc [60]. LRP1 is a transmembrane endocytic receptor that mediates the endocytosis of exogenous substances, and consisted of three regions: extracellular region, transmembrane region and intracellular region. It is broadly expressed in human body cells and high levels of distribution in the brain and lungs [61]. This highly expression of LRP1 in BBB suggests that LDL receptor-mediated internalization is a viable route for targeted drug delivery in the brain [62].