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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).
The Role of Plasminogen Activator Inhibitor Type 1 (PAI-1) in the Clinical Setting, Including Deep Vein Thrombosis
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Although no particular hormone, cytokine, or growth factor has been identified so far that is responsible for the circadian rhythm of PAI-1, there is ample evidence that many of these factors upregulate PAI-1 expression, which usually takes place on a transcriptional level and is well summarized in several recent reviews65,66 and in Chapter 3 by Lawrence and Ginsburg. It is interesting to note that patients with high PAI-1 levels usually also have high t-PA levels and the question arises whether both of these components are regulated, in part, by the same pathway or whether high t-PA levels in the plasma induce the expression of PAI-1, or vice versa. Fujii and Sobel68 have added excess t-PA to cultures of HepG2 and of human umbilical endothelial cells. Bom of these cell lines constitutively express PAI-1. Addition of t-PA caused an increase of PAI-1 in the conditioned medium. Northern blot analysis revealed that mRNA expression was increased twofold, supporting the conclusion that t-PA caused an increase of transcriptional expression.67 This effect was attributable to the protease part of t-PA.68 It is possible that the trigger for increased PAI-1 expression is binding of t-PA to cell surface-bound PAI-1 or to the low density lipoprotein receptor-related protein receptor (LRP),69-71 internalization and activation of an intracellular signal transmission pathway.
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).
Development of an apolipoprotein E mimetic peptide–lipid conjugate for efficient brain delivery of liposomes
Published in Drug Delivery, 2023
Naoya Kato, Sakura Yamada, Rino Suzuki, Yoshiki Iida, Makoto Matsumoto, Shintaro Fumoto, Hidetoshi Arima, Hidefumi Mukai, Shigeru Kawakami
In the in vivo evaluation of the brain-targeting efficiency under various conditions, including the influence of the presence of blood components, the trends in efficiency obtained with in situ brain perfusion and systemic administration systems were similar, with ApoEdp being the most efficient (Figure 3). Regarding the sensitivity of detecting differences in the brain-targeting ability of peptides, the in situ perfusion system is better, as the effect of systemic biodistribution is ignored. Because of the slow clearance of PEGylated liposomes, it is appropriate to discuss the result in a perfusion system, which can be assessed the first-pass effect of peptides on the brain. The high brain-targeting efficiency of ApoEdp may be due to its ability to target multiple receptors, including LDLR, low-density lipoprotein receptor-related protein (LRP)-1, and LRP-2. Most importantly, Histological studies demonstrated that ApoEdp can leak from the cerebral blood vessels and distribute in the brain parenchyma (Figure 4); therefore, we selected ApoEdp as the peptide for PEGylated liposome modification.
A critical review on the role of nanotheranostics mediated approaches for targeting β amyloid in Alzheimer’s
Published in Journal of Drug Targeting, 2023
Vaibhav Rastogi, Anjali Jain, Prashant Kumar, Pragya Yadav, Mayur Porwal, Shashank Chaturvedi, Phool Chandra, Anurag Verma
In AD, BBB disruption prevents amyloid β transfer from the brain to the peripheral circulation. Lower LRP-1 (low-density lipoprotein receptor-related protein 1) and higher RAGE (receptor for advanced glycation end products) levels make the BBB more prone to amyloid β transport failure. BBB pericytes, astrocytes, vascular endothelial cells, and tight junctions are involved in AD pathogenesis [28]. Along with that, the BBB dysfunction increases the activity of the β-secretase and у-secretase and increases the formation of the Amyloid-β. Accelerating the accumulation of Amyloid-β in the brain and initiating cognitive impairment, causes AD. Fundamentally, BBB dysfunction affects the proper clearance of the Amyloid-β from the CNS to PNS [26]. Also, the BBB dysfunction indirectly clears the way for tau hyperphosphorylation, leading to BBB damage. This tau hyperphosphorylation causes the formation of the NFT (Neurofibrillary tangles, composed of the microtubules of protein tau), commonly occurring in a patient with AD [23].
An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia
Published in Expert Review of Neurotherapeutics, 2021
Siddhartha Dutta, Sayeeda Rahman, Rahnuma Ahmad, Tarun Kumar, Gitashree Dutta, Sudeshna Banerjee, Abdullahi Rabiu Abubakar, Adekunle Babajide Rowaiye, Sameer Dhingra, Velayutham Ravichandiran, Santosh Kumar, Paras Sharma, Mainul Haque, Jaykaran Charan
The study by Sagare AP et al. suggested that statins might not decrease the production of Aβ. Instead, it can enhance the expression of low-density lipoprotein receptor-related protein-1 (LRP1), a crucial cell surface receptor responsible for the clearance of brain and systemic amyloid-beta AD, facilitating the efflux of Aβ from the brain [169]. In a few studies on transgenic mice, some statins like simvastatin and lovastatin have been seen to affect the PI3K/Akt pathway, further blocking the proapoptotic action of the p38 MAPK pathway, consequently restoring the normal neuronal function in early AD and preventing the neurons from death [170–173]. Similar results are also supported by pitavastatin in the in vitro studies where the statin seemed to modulate membrane distribution by Rho proteins and further diminish tau protein levels [169]. The benefits of statin therapy to reduce the risk of dementia are summarized in Table 2 [7,134,135,154,174–183]. The findings of studies showing no association of statin therapy with dementia are summarized in Table 3 [184–191].