Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice

Wang, Lei; Wang, Zi; Shi, Jiandang; Jiang, Qian; Wang, Hong; Xu, Li; Hao, Dejun

doi:10.3892/ijmm.2018.3797

Cited by 19 publications

(24 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In APOE (−/−) mice fed with a high-fat diet, the hippocampal neuronal apoptosis was associated with an increase of PCSK9 expression (Zhao et al, 2017). Consistently, silencing of PCSK9 attenuates the neuronal apoptosis induced by cerebral ischemia reducing brain damage in mice (Wang et al, 2018). Conversely, a preventive action of PCSK9 on neuronal apoptosis may occur through the decrease in Aβ generation (Wu et al, 2014).…”

Section: Pcsk9 and Alzheimer’s Disease Pathogenesismentioning

confidence: 71%

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease

Adorni

Ruscica

Ferri

et al. 2019

Front. Aging Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.

show abstract

Section: Pcsk9 and Alzheimer’s Disease Pathogenesismentioning

confidence: 71%

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease

Adorni

Ruscica

Ferri

et al. 2019

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…Furthermore, mice fed with HFD showed upregulated serum lipid levels and PCSK9 expression in both the liver and brain. Upon middle cerebral artery occlusion to mimic ischemic stroke, the hyperlipidemic mice exhibited enhanced neuronal apoptosis, cerebral injury, PCSK9, and ApoER2 levels in the brain, which was abrogated by inhibition of PCSK9 using short-hairpin RNA targeting PCSK9 to the cerebral cortex [121]. Hyperlipidemia is highly associated with inflammatory processes, making inflammation a critical modulator in the development of atherosclerotic cardiovascular diseases (ASCVDs).…”

Section: Gut-liver-brain Axismentioning

confidence: 99%

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder

Lee

O’Connell

Pacher

et al. 2021

JCM

View full text Add to dashboard Cite

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.

show abstract

“…In the case of the VLDL receptor, PCSK9 is not involved in its regulation ( Kysenius and Huttunen, 2016 ). However, PCSK9 may trigger apoptosis via ApoER2 but the subsequent intracellular pathways are not yet identified ( Kysenius et al, 2012 ; Wang et al, 2018 ). Thus, it seems that PCSK9 target molecules differ between the brain and liver.…”

Section: The Role Of Pcsk9 In the Brainmentioning

confidence: 99%

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

2020

View full text Add to dashboard Cite

Neuronal apoptosis regulated convertase-1 (NARC-1), now mostly known as proprotein convertase subtilisin/kexin type 9 (PCSK9), has received a lot of attention due to the fact that it is a key regulator of the low-density lipoprotein (LDL) receptor (LDL-R) and is therefore involved in hepatic LDL clearance. Within a few years, therapies targeting PCSK9 have reached clinical practice and they offer an additional tool to reduce blood cholesterol concentrations. However, PCSK9 is almost ubiquitously expressed in the body but has less well-understood functions and target proteins in extra hepatic tissues. As such, PCSK9 is involved in the regulation of neuronal survival and protein degradation, it affects the expression of the epithelial sodium channel (ENaC) in the kidney, it interacts with white blood cells and with cells of the vascular wall, and it modifies contractile activity of cardiomyocytes, and contributes to the regulation of cholesterol uptake in the intestine. Moreover, under stress conditions, signals from the kidney and heart can affect hepatic expression and thereby the plasma concentration of PCSK9 which then in turn can affect other target organs. Therefore, there is an intense relationship between the local (autocrine) and systemic (endocrine) effects of PCSK9. Although, PCSK9 has been recognized as a ubiquitously expressed modifier of cellular function and signaling molecules, its physiological role in different organs is not well-understood. The current review summarizes these findings.

show abstract

Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice

Cited by 19 publications

References 24 publications

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

Contact Info

Product

Resources

About