Anti‐PCSK 9 antibodies increase the ratios of the brain‐specific oxysterol 24S‐hydroxycholesterol to cholesterol and to 27‐hydroxycholesterol in the serum

Lütjohann, Dieter; Stellaard, Frans; Bölükbasi, Bediha; Kerksiek, Anja; Parhofer, Klaus G.; Laufs, Ulrich

doi:10.1111/bcp.14841

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…113 One study demonstrated increased excretion of 24S-hydroxycholesterol from the brain in response to PCSK9 inhibitor therapy. 114 Whether inclisiran, an siRNA that inhibits the translation of the PCSK9 mRNA, crosses the BBB is not known. 115 PCSK9 inhibitors, through an increase in LDL receptors, could theoretically increase brain absorption of cholesterol from the periphery.…”

Section: Brain Metabolism Of Cholesterol and Potential Effect Of Chol...mentioning

confidence: 99%

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association

Goldstein,

Toth,

Dearborn-Tomazos

et al. 2023

ATVB

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The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.

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Section: Brain Metabolism Of Cholesterol and Potential Effect Of Chol...mentioning

confidence: 99%

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association

Goldstein,

Toth,

Dearborn-Tomazos

et al. 2023

ATVB

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“…The effects of evolocumab and alirocumab on lipidome profile were evaluated in hypercholesterolemic patients responding insufficiently to maximally tolerated statin and/or ezetimibe therapy. The brain-specific oxysterols 24S-OHC and 27-OHC were assessed by isotope dilution GC-MS selected ion-monitoring (GC–MS-SIM) by using the corresponding deuterium-labelled oxysterols as internal standards, before, after 1-month and after 3-month of treatment ( 91 ). 24S-OHC ratios to cholesterol and to 27-OHC in serum or plasma are thought to be potential biomarkers for brain cholesterol metabolism ( 92 ).…”

Section: Agnostic Evaluation Of Pcsk9 Effects By Proteomics and Lipid...mentioning

confidence: 99%

“…24S-OHC ratios to cholesterol and to 27-OHC in serum or plasma are thought to be potential biomarkers for brain cholesterol metabolism ( 92 ). After 1-month of treatment, evolocumab and alirocumab significantly reduced serum total cholesterol, LDL-C and 27-OHC concentrations, whereas serum ratios of 24S-OHC to cholesterol and 24S-OHC to 27-OHC increased, reaching even higher levels within 3 months of treatment ( 91 ). The authors suggested that this specific brain cholesterol turnover was probably due to lower levels of 27-OHC in the brain, resulting in increased synthesis of brain cholesterol, higher production of 24S-OHC and its secretion across the blood-brain barrier.…”

Section: Agnostic Evaluation Of Pcsk9 Effects By Proteomics and Lipid...mentioning

confidence: 99%

Proteomics and Lipidomics to unveil the contribution of PCSK9 beyond cholesterol lowering: a narrative review

Gianazza

Macchi

Banfi

et al. 2023

Front. Cardiovasc. Med.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of the low-density lipoprotein receptor (LDLR), can play a direct role in atheroma development. Although advances in the understandings of genetic PCSK9 polymorphisms have enabled to reveal the role of PCSK9 in the complex pathophysiology of cardiovascular diseases (CVDs), increasing lines of evidence support non-cholesterol-related processes mediated by PCSK9. Owing to major improvements in mass spectrometry-based technologies, multimarker proteomic and lipidomic panels hold the promise to identify novel lipids and proteins potentially related to PCSK9. Within this context, this narrative review aims to provide an overview of the most significant proteomics and lipidomics studies related to PCSK9 effects beyond cholesterol lowering. These approaches have enabled to unveil non-common targets of PCSK9, potentially leading to the development of novel statistical models for CVD risk prediction. Finally, in the era of precision medicine, we have reported the impact of PCSK9 on extracellular vesicles (EVs) composition, an effect that could contribute to an increased prothrombotic status in CVD patients. The possibility to modulate EVs release and cargo could help counteract the development and progression of the atherosclerotic process.

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Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum

Papotti,

Palumbo,

Adorni

et al. 2024

Journal of Alzheimer’s Disease

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Background Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified. Objective We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype. Methods We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. Results CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = −0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = −0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients. Conclusions PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum.

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Anti‐PCSK 9 antibodies increase the ratios of the brain‐specific oxysterol 24S‐hydroxycholesterol to cholesterol and to 27‐hydroxycholesterol in the serum

Cited by 3 publications

References 51 publications

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association

Proteomics and Lipidomics to unveil the contribution of PCSK9 beyond cholesterol lowering: a narrative review

Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum

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