HMGB1/RAGE/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis

Abuelezz, Sally A.; Hendawy, Nevien

doi:10.1016/j.lfs.2021.119310

Cited by 27 publications

(24 citation statements)

References 41 publications

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“…Interestingly, the association between PCSK9 and Alzheimer’s disease (AD) in the literature remains unclear. One of the canonical features of AD pathology is the accumulation of amyloid β (Aβ) plaque as a result of changes in the pathways responsible for Aβ; namely, the pathways regulated by the amyloid precursor protein (APP) and β secretase-1 (BACE1) [ 99 ]. BACE1, in particular, is known to play a major role in the development of AD due to its ability to clear Aβ.…”

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

“…BACE1, in particular, is known to play a major role in the development of AD due to its ability to clear Aβ. Studies investigating AD pathophysiology in the last decade have uncovered a significant connection between AD and dyslipidemia [ 99 , 100 ]. Interestingly, PCSK9 was shown to decrease cholesterol uptake in the brain by degrading the LDLR-related protein-1 (LRP1), and subsequently decreasing Aβ clearance [ 100 ].…”

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

“…Interestingly, PCSK9 was shown to decrease cholesterol uptake in the brain by degrading the LDLR-related protein-1 (LRP1), and subsequently decreasing Aβ clearance [ 100 ]. Abuelezz and colleagues investigated the impact of PCSK9-inhibitor alirocumab in brain cholesterol metabolism, dyslipidemia, and neuroinflammation, which are markers of AD risk and pathology [ 99 ]. Results demonstrated a significant association between inhibition of PCSK9 and reduction of neuroinflammatory markers in rat models of AD [ 99 ].…”

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

“…Abuelezz and colleagues investigated the impact of PCSK9-inhibitor alirocumab in brain cholesterol metabolism, dyslipidemia, and neuroinflammation, which are markers of AD risk and pathology [ 99 ]. Results demonstrated a significant association between inhibition of PCSK9 and reduction of neuroinflammatory markers in rat models of AD [ 99 ]. Alirocumab-treated groups presented with increased LRP1 expression levels as well as reduced brain cholesterol levels, and neuroinflammatory marker expression including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) [ 99 ].…”

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

“…Results demonstrated a significant association between inhibition of PCSK9 and reduction of neuroinflammatory markers in rat models of AD [ 99 ]. Alirocumab-treated groups presented with increased LRP1 expression levels as well as reduced brain cholesterol levels, and neuroinflammatory marker expression including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) [ 99 ]. Hippocampal BACE1, associated with Aβ clearance, was also reduced [ 99 ].…”

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

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The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases

et al. 2022

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The importance of the proprotein convertase subtilisin/kexin type-9 (PCSK9) gene was quickly recognized by the scientific community as the third locus for familial hypercholesterolemia. By promoting the degradation of the low-density lipoprotein receptor (LDLR), secreted PCSK9 protein plays a vital role in the regulation of circulating cholesterol levels and cardiovascular disease risk. For this reason, the majority of published works have focused on the secreted form of PCSK9 since its initial characterization in 2003. In recent years, however, PCSK9 has been shown to play roles in a variety of cellular pathways and disease contexts in LDLR-dependent and -independent manners. This article examines the current body of literature that uncovers the intracellular and LDLR-independent roles of PCSK9 and also explores the many downstream implications in metabolic diseases.

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Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

Section: Pcsk9 and Neurodegenerative Diseasementioning

confidence: 99%

See 3 more Smart Citations

The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases

et al. 2022

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Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside

et al. 2021

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PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1

Hendawy

Salaheldin

Abuelezz

2023

J Neuroimmune Pharmacol

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Ample evidence has pointed to a close link between cardiovascular diseases (CVD) and depression. Inflammatory pathways including the high-mobility-group-box-1 protein, receptor-for-advanced-glycation-end-products and toll-like-receptor-4 (HMGB1/RAGE/TLR4) and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathways are thought to be crucial players in this link. Activation of these pathways ends by releasing of different inflammatory mediators involved in CVD and depression pathophysiology. In the brain, this inflammatory process enhanced indoleamine2,3-dioxygenase-1 (IDO-1) activation with subsequent alteration in kynurenine/tryptophan levels causing depression. Based on the favorable anti-inflammatory effects of Alirocumab, the proprotein-convertase-subtilisin/kexin-type-9 (PCSK9) inhibitor, used in different CVD, this study was designed to investigate its potential antidepressant effect. The behavioral and neurochemical effects of concomitant treatment of Alirocumab at doses of (4, 8 and 16 mg/kg/week subcutaneously) in Wistar rats exposed to chronic unpredictable mild stress (CUMS) for 6 weeks were assayed. Alirocumab prevented CUMS-induced depressive-like-behaviors exhibited in open-field and forced-swimming tests, and hypothalamus–pituitary–adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Alirocumab prevented CUMS-induced alteration in hippocampal kynurenine/tryptophan levels and pro-inflammatory cytokines tumor-necrosis-factor-alpha, interleukin-1beta (IL-1β), IL-2 and IL-6. Western blot and PCR analysis showed that Alirocumab favorably modulated the HMGB1/RAGE/TLR4 axis, nuclear-factor-kappa-beta, NLRP3 inflammasome complex and IDO-1 in the hippocampus of CUMS rats. These effects were correlated to the level of PCSK9 expression. The behavioral and biochemical findings indicated the potential antidepressant effect of PCSK9 inhibition by Alirocumab. Graphical Abstract

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HMGB1/RAGE/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis

Cited by 27 publications

References 41 publications

The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases

The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases

Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside

PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1

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