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Lipids in Neurodegenerative Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 25452

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Prof. Dr. Giuseppe Sancesario

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Dipartimento di Medicina dei Sistemi, Università di Roma 2 Tor Vergata, 00133 Roma, Italy
Interests: Alzheimer’s disease; Parkinson disease; dystonia, movement disorders; neuropathology, proteinopathy; oligomers; lipids in neurodegenerative diseases

Dr. Valerio Chiurchiù

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Guest Editor

1. Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, Italy
2. Laboratory of Resolution of Neuroinflammation, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, 00143 Rome, Italy
Interests: bioactive lipids; specialized proresolving lipid mediators (SPMs); immunology; innate and adaptive immunity; neuroinflammation; glial cells; multiple sclerosis (MS)
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Dear Colleagues,

Proteopathy (protein disease) is a term coined by Walker and LeVine (Neurobiology of Aging 21, 559–561, 2000) to define disparate diseases of the nervous system, characterized by malfunctioning endogenous protein monomers becoming conformationally unstable, prone to self-polymerize in small and large aggregates, known as oligomers and fibrils, producing neuronal damage. Each specific protein, in acquiring a strong tendency to self-aggregate, regardless of its physiological function, can underline a specific neurodegenerative process. Some of the most common neurodegenerative proteopathies are Alzheimer’s disease (AD), Parkinson’s disease (PD), Creutzfeldt–Jacob disease (CJD), dementia with Lewy bodies (DLB), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS).

In recent decades, compelling evidence has demonstrated that oligomers are toxic and per se sufficient to induce a pathological cascade involving the cell membrane, mitochondrial damage, and reactive inflammation, finally leading to degeneration of the central nervous system; by contrast, fibrillar large aggregates may be relatively benign.

Many efforts have been made to understand factors leading to proteins’ conformational changes. In some instances, proteins’ instability and increased tendency to polymerize are due to point mutations in the encoding genes, which are responsible for the familial hereditary forms of neurodegenerative diseases. However, the most prevalent cases of typical proteopathies are of unknown origin. In recent years, a lot of studies have focused on lipids, constituting globally about 50% of brain tissue, and on the multidimensional roles that they may have in the pathogenic processes of common neurodegenerative diseases.

It has been shown that lipids can interact particularly with the aggregation and propagation of pathogenic proteins, e.g., amyloid-β, tau, and α-synuclein, underlying the neurodegenerative processes of AD, FTD, PD, and DLB. Moreover, lipids can influence other key aspects of neurodegenerative disease pathophysiology, which are mitochondrial dysfunction, inflammation, and oxidative stress.

This Special Issue on “Lipids in Neurodegenerative Diseases” aims to collect original research and review articles on the multifaceted role that lipids may have on differentiated pathophysiological cascades, leading to the most common as well as to less common neurodegenerative proteopathies.

Prof. Dr. Giuseppe Sancesario
Dr. Valerio Chiurchiù
Guest Editors

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Keywords

neuron
astrocytes
microglia
neurodegeneration
protein folding
Alzheimer’s disease
Parkinson’s disease
dementia with Lewy bodies
amyotrophic lateral sclerosis
Huntington disease
Creutzfeldt–Jacob disease
amyloid precursor protein
amyloid-β
tau
α-synuclein
oligomers
fibrils
lipids
apolipoproteins
lipoproteins
lipoprotein receptors
blood–brain barrier
energy metabolism
oxidative stress
inflammation
mitochondria
myelination

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Published Papers (9 papers)

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Editorial

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3 pages, 204 KiB

Open AccessEditorial

Lipids in Neurodegenerative Diseases

by Valerio Chiurchiù

Int. J. Mol. Sci. 2023, 24(14), 11523; https://doi.org/10.3390/ijms241411523 - 16 Jul 2023

Viewed by 1456

Abstract

Lipids are undoubtedly the major constituents of the cell membranes of all living organisms, and the most efficient source of energy [...] Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

Research

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12 pages, 3388 KiB

Open AccessArticle

Convenient and Sensitive Measurement of Lactosylceramide Synthase Activity Using Deuterated Glucosylceramide and Mass Spectrometry

by Michele Dei Cas, Linda Montavoci, Sara Casati, Nadia Malagolini, Fabio Dall’Olio and Marco Trinchera

Int. J. Mol. Sci. 2023, 24(6), 5291; https://doi.org/10.3390/ijms24065291 - 10 Mar 2023

Cited by 2 | Viewed by 1776

Abstract

Lactosylceramide is necessary for the biosynthesis of almost all classes of glycosphingolipids and plays a relevant role in pathways involved in neuroinflammation. It is synthesized by the action of galactosyltransferases B4GALT5 and B4GALT6, which transfer galactose from UDP-galactose to glucosylceramide. Lactosylceramide synthase activity was classically determined in vitro by a method based on the incorporation of radiolabeled galactose followed by the chromatographic separation and quantitation of the product by liquid scintillation counting. Here, we used deuterated glucosylceramide as the acceptor substrate and quantitated the deuterated lactosylceramide product by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We compared this method with the classical radiochemical method and found that the reactions have similar requirements and provide comparable results in the presence of high synthase activity. Conversely, when the biological source lacked lactosylceramide synthase activity, as in the case of a crude homogenate of human dermal fibroblasts, the radiochemical method failed, while the other provided a reliable measurement. In addition to being very accurate and sensitive, the proposed use of deuterated glucosylceramide and LC-MS/MS for the detection of lactosylceramide synthase in vitro has the relevant advantage of avoiding the costs and discomforts of managing radiochemicals. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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16 pages, 9254 KiB

Open AccessArticle

Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily

by Yaroslav V. Bershatsky, Andrey S. Kuznetsov, Aisha R. Idiatullina, Olga V. Bocharova, Sofya M. Dolotova, Alina A. Gavrilenkova, Oxana V. Serova, Igor E. Deyev, Tatiana V. Rakitina, Olga T. Zangieva, Konstantin V. Pavlov, Oleg V. Batishchev, Vladimir V. Britikov, Sergey A. Usanov, Alexander S. Arseniev, Roman G. Efremov and Eduard V. Bocharov

Int. J. Mol. Sci. 2023, 24(4), 3906; https://doi.org/10.3390/ijms24043906 - 15 Feb 2023

Cited by 3 | Viewed by 2780

Abstract

Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions. In this work, using high-resolution NMR spectroscopy supported by atomistic computer modeling, conformational variability of the transmembrane domains and their interactions with surrounding lipids were found to differ significantly between representatives of the subfamily. Therefore, we suggest that the heterogeneous and highly dynamic membrane environment should be taken into account in the observed diversity of the structural/dynamic organization and mechanisms of activation of InsR, IGF1R, and IRR receptors. This membrane-mediated control of receptor signaling offers an attractive prospect for the development of new targeted therapies for diseases associated with dysfunction of insulin subfamily receptors. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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8 pages, 441 KiB

Open AccessCommunication

A Metabolic Signature of Hereditary Transthyretin Amyloidosis: A Pilot Study

by Marco Luigetti, Valeria Guglielmino, Angela Romano, Maria Ausilia Sciarrone, Francesca Vitali, Andrea Sabino, Jacopo Gervasoni, Aniello Primiano, Lavinia Santucci, Rossana Moroni and Guido Primiano

Int. J. Mol. Sci. 2022, 23(24), 16133; https://doi.org/10.3390/ijms232416133 - 17 Dec 2022

Cited by 4 | Viewed by 1762

Abstract

Hereditary transthyretin amyloidosis is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. ATTRv amyloidosis can present as a progressive, axonal sensory autonomic and motor neuropathy or as an infiltrative cardiomyopathy. The definition of biomarkers for the early diagnosis of ATTRv is particularly important in the current era of emerging treatments. In this sense, metabolomics could be an instrument able to provide metabolic profiles with their related metabolic pathways, and we would propose them as possible fluid biomarkers. The aim of this study is to identify altered metabolites (free fatty acids and amino acids) in subjects with a confirmed pathogenic TTR variant. Out of the studied total free fatty acids and amino acids, the serum values of palmitic acid are significantly lower in the ATTRv patients compared to the recruited healthy subjects. The metabolic remodeling identified in this neurogenetic disorder could be the manifestation of pathophysiological processes of the disease, such as mitochondrial dysfunction and neuroinflammation, and contribute to explaining some of its clinical manifestations. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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18 pages, 3322 KiB

Open AccessArticle

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

by Bianca Papotti, Maria Pia Adorni, Cinzia Marchi, Francesca Zimetti, Nicoletta Ronda, Giovanni Panighel, Maria Giovanna Lupo, Antonietta Vilella, Daniela Giuliani, Nicola Ferri and Franco Bernini

Int. J. Mol. Sci. 2022, 23(20), 12192; https://doi.org/10.3390/ijms232012192 - 13 Oct 2022

Cited by 12 | Viewed by 2687

Abstract

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer’s disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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9 pages, 1302 KiB

Open AccessCommunication

GM1 Is Cytoprotective in GPR37-Expressing Cells and Downregulates Signaling

by Ellen Hertz, Marcus Saarinen and Per Svenningsson

Int. J. Mol. Sci. 2021, 22(23), 12859; https://doi.org/10.3390/ijms222312859 - 27 Nov 2021

Cited by 5 | Viewed by 2373

Abstract

G-protein-coupled receptors (GPCRs) are commonly pharmacologically modulated due to their ability to translate extracellular events to intracellular changes. Previously, studies have mostly focused on protein–protein interactions, but the focus has now expanded also to protein–lipid connections. GM1, a brain-expressed ganglioside known for neuroprotective effects, and GPR37, an orphan GPCR often reported as a potential drug target for diseases in the central nervous system, have been shown to form a complex. In this study, we looked into the functional effects. Endogenous GM1 was downregulated when stably overexpressing GPR37 in N2a cells (N2a^GPR37-eGFP). However, exogenous GM1 specifically rescued N2a^GPR37-eGFP from toxicity induced by the neurotoxin MPP+. The treatment did not alter transcription levels of GPR37 or the enzyme responsible for GM1 production, both potential mechanisms for the effect. However, GM1 treatment inhibited cAMP-dependent signaling from GPR37, here reported as potentially consecutively active, possibly contributing to the protective effects. We propose an interplay between GPR37 and GM1 as one of the many cytoprotective effects reported for GM1. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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Review

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16 pages, 1050 KiB

Open AccessReview

Lipoprotein Metabolism, Protein Aggregation, and Alzheimer’s Disease: A Literature Review

by Elena Grao-Cruces, Carmen M. Claro-Cala, Sergio Montserrat-de la Paz and Clevio Nobrega

Int. J. Mol. Sci. 2023, 24(3), 2944; https://doi.org/10.3390/ijms24032944 - 2 Feb 2023

Cited by 5 | Viewed by 3027

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features: amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role; however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain; apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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27 pages, 605 KiB

Open AccessReview

Lipidomics of Bioactive Lipids in Alzheimer’s and Parkinson’s Diseases: Where Are We?

by Valerio Chiurchiù, Marta Tiberi, Alessandro Matteocci, Federico Fazio, Hasibullah Siffeti, Stefano Saracini, Nicola Biagio Mercuri and Giuseppe Sancesario

Int. J. Mol. Sci. 2022, 23(11), 6235; https://doi.org/10.3390/ijms23116235 - 2 Jun 2022

Cited by 30 | Viewed by 4936

Abstract

Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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13 pages, 1436 KiB

Open AccessReview

Neurodegenerative Disorders: Spotlight on Sphingolipids

by Frida Mandik and Melissa Vos

Int. J. Mol. Sci. 2021, 22(21), 11998; https://doi.org/10.3390/ijms222111998 - 5 Nov 2021

Cited by 20 | Viewed by 3372

Abstract

Neurodegenerative diseases are incurable diseases of the nervous system that lead to a progressive loss of brain areas and neuronal subtypes, which is associated with an increase in symptoms that can be linked to the affected brain areas. The key findings that appear in many neurodegenerative diseases are deposits of proteins and the damage of mitochondria, which mainly affect energy production and mitophagy. Several causative gene mutations have been identified in various neurodegenerative diseases; however, a large proportion are considered sporadic. In the last decade, studies linking lipids, and in particular sphingolipids, to neurodegenerative diseases have shown the importance of these sphingolipids in the underlying pathogenesis. Sphingolipids are bioactive lipids consisting of a sphingoid base linked to a fatty acid and a hydrophilic head group. They are involved in various cellular processes, such as cell growth, apoptosis, and autophagy, and are an essential component of the brain. In this review, we will cover key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases and will focus on neurodegeneration with brain iron accumulation and Parkinson’s disease. Full article

(This article belongs to the Special Issue Lipids in Neurodegenerative Diseases)

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