Potential Link Between Proprotein Convertase Subtilisin/Kexin Type 9 and Alzheimer’s Disease

Ce, Oldham; Rs, Powell; Ab, Williams; Dixon, Scott J.; Cj, Wooten; Qm, Melendez; Lopez, Dayami

doi:10.31531/2581-4745.1000106

Cited by 4 publications

(2 citation statements)

References 209 publications

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“…One alternative possibility on how LDL-C, PCSK9, and AD are linked to each other may be that PCSK9 contributes to vascular stress (see below) that then affects the blood-brain barrier and favors inflammation ( Zhao et al, 2016 ). Other potential PCSK9 target molecules that may affect AD are VLDL receptors and CD36 ( Oldham et al, 2018 ). However, as the neuronal expressions of them are not affected by PCSK9 deficiency in mice such an interaction remains unclear at the moment.…”

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

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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.

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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

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“…7 PCSK9 also appears to regulate the development of glucose intolerance, insulin resistance, abdominal obesity, inflammation and hypertension, conditions that have been identified as risk factors for AD. 8 Recently it was found that PCSK9 is elevated in the cerebrospinal fluid (CSF) of individuals with alcohol use disorders. Therefore, inhibition of PCSK9 is discussed as a new therapeutic target for alcoholic liver disease.…”

Section: Introductionmentioning

confidence: 99%

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

Lütjohann

Stellaard

Bölükbasi

et al. 2021

Brit J Clinical Pharma

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Aims:The serum ratios of the brain-specific oxysterol 24S-hydroxycholesterol (24S-OHC) to cholesterol and to 27-OHC reflect brain cholesterol turnover. We studied the effect of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) that enhance low-density lipoprotein receptor activity on serum cholesterol and oxysterol concentrations.Methods: Twenty-eight hypercholesterolaemic patients (15 males and 13 females) responding insufficiently to maximally tolerated statin and/or ezetimibe therapy were additionally subcutanously treated biweekly with either the PCSK9ab alirocumab (150 mg, n = 13) or evolocumab (140 mg, n = 15). Fasting serum cholesterol was measured by gas chromatography and the oxysterols 24S-OHC and 27-OHC using gas chromatography-mass spectrometry before, after 1-month (n = 28) and after 3-month (n = 13) treatment.

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No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab

et al. 2022

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APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer’s disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p’s>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer’s disease.

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Potential Link Between Proprotein Convertase Subtilisin/Kexin Type 9 and Alzheimer’s Disease

Cited by 4 publications

References 209 publications

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

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

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

No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab

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