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The potential of lipid nutrients to prevent Parkinson's and Alzheimer's disease. Several lipid nutrients, including vegetable and animal oils, functionalized oils and fatty acids, could be used to treat or attenuate Parkinson's and Alzheimer's disease. These disorders have in common protein aggregation and the alteration of protein degradation systems, which can trigger mitochondrial dysfunction and oxidative stress, leading to cell death and inflammation. There are now several in vitro and in vivo arguments that lipid nutrients can be efficient in the prevention of neurodegeneration associated with protein aggregation (β-amyloids in Alzheimer's disease and
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Neurodegenerative diseases, particularly Parkinson's and Alzheimer's, have common features: protein accumulation, cell death with mitochondrial involvement and oxidative stress. Patients are treated to cure the symptoms, but the treatments do not target the causes; so, the disease is not stopped. It is interesting to look at the side of nutrition w...
Context in source publication
Context 1
... prevent these side effects, some nutrients could be used as nutraceuticals or a as part of functionalized foods. There are indeed several lines of evidence that oils and fatty acids used alone could be employed because of their actions on protein aggregation, dysfunctional protein degradation systems, cell death, oxidative stress and/or inflammation to prevent or slow down the development of these diseases (Figure 2). Furthermore, interactions between nutraceutical products could have inverse, negative results; it is important not to value the additive or synergistic effects of combination products in vivo without testing them in animal models and human clinical studies. ...
Citations
... On the one hand, HMGCR is known to be a proinflammatory compound that upregulates MHC-II expression to activate T-cell activation, thereby increasing the release of the proinflammatory cytokines Interleukin-1 (IL-1) and IL-6 and the synthesis of TNF-α [73,74]. ...
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.
... The use of docosahexaenoic acid (DHA) inhibits VLCFA-induced toxicity [11]. Two reviews also considered the potential use of nutraceuticals (e.g., antioxidants) or dietary lipids in the form of animal or vegetable oils or fatty acids [12,13]. ...
A neurodegenerative disease is a pathological condition affecting neurons, condemning them to death [...]
... Much more studies have shown that lipid metabolism is involved in the occurrence and development of a variety of neurodegenerative diseases, especially in the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD) (Nury et al., 2020). But the mechanism that abnormal lipid metabolism leads to neurodegenerative diseases has long been a mystery. ...
Lipids are a class of complex hydrophobic molecules derived from fatty acids that not only form the structural basis of biological membranes but also regulate metabolism and maintain energy balance. The role of lipids in obesity and other metabolic diseases has recently received much attention, making lipid metabolism one of the attractive research areas. Several metabolic diseases are linked to lipid metabolism, including diabetes, obesity, and atherosclerosis. Additionally, lipid metabolism contributes to the rapid growth of cancer cells as abnormal lipid synthesis or uptake enhances the growth of cancer cells. This review introduces the potential drug targets in lipid metabolism and summarizes the important potential drug targets with recent research progress on the corresponding small molecule inhibitor drugs. The significance of this review is to provide a reference for the clinical treatment of metabolic diseases related to lipid metabolism and the treatment of tumors, hoping to deepen the understanding of lipid metabolism and health.
... Exponential oxidative stress, together with DNA mutation, leads to mitochondria dysfunction which is much implicated in the aging process (18). In AD, oxidative stress leads to the activation of amyloidogenesis pathway which elevates the development and deposition of amyloid peptide (19). Equally in PD, oxidative stress leads to misfolding of α-synuclein protein that causes neurodegeneration; loss of dopaminergic neurons and loss of dopamine in the brain (20). ...
Neurodegenerative disorders, such as Parkinson's and Alzheimer's disease, are claimed to be of major concern causing a significant disease burden worldwide. Oxidative stress, mitochondrial dysfunction and nerve damage are the main reasons for the emergence of these diseases. The formation of reactive oxygen species (ROS) is the common chemical molecule that is formed from all these three interdependent mechanisms which is highly reactive toward the neuronal cells. For these reasons, the administration of tocotrienols (T3s), which is a potent antioxidant, is proven to cater to this problem, through in vitro and in vivo investigations. Interestingly, their therapeutic potentials are not only limited to antioxidant property but also to being able to reverse the neuronal damage and act as a shield for mitochondria dysfunction. Thereby, T3s prevents the damage to the neurons. In regards to this statement, in this review, we focused on summarizing and discussing the potential therapeutic role of T3s on Alzheimer's and Parkinson's diseases, and their protective mechanisms based on evidence from the in vitro and in vivo studies. However, there is no clinical trial conducted to prove the efficacy of T3s for Alzheimer's and Parkinson's subjects. As such, the therapeutic role of T3s for these neurodegenerative disorders is still under debate.
... The generated fragments including Ab 1-40 and Ab aggregates are recognized to be the most toxic types, which are accumulated extracellularly to form Ab fibrils and ultimately form senile plaque in the brain of AD patients 7 . In the early state of AD, Ab can still be cleared through the autophagy-lysosome pathway (ALP) 8 and the ubiquitinÀproteasome pathway (UPP) in neurons or engulfed by microglia 9 . However, both ALP and UPP are dysregulated with age, and the clearance of Ab cannot be executed effectively 10 . ...
Discovery of drugs rapidly and effectively is an important aspect for Alzheimer’s disease (AD). In this study, a novel high-throughput screening (HTS) method aims at screening the small-molecules with amyloid-β (Aβ) binding affinity from natural medicines, based on the combinational use of biolayer interferometry (BLI) and ultra-high-performance liquid chromatography coupled with diode-array detector and quadrupole/time-of-flight tandem mass spectrometry (UHPLC−DAD-Q/TOF-MS/MS) has been firstly developed. Briefly, the components in natural medicines disassociated from biotinylated Aβ were collected to analyze their potential Aβ binding affinity by UHPLC−DAD-Q/TOF-MS/MS. Here, baicalein was confirmed to exhibit the highest binding affinity with Aβ in Scutellaria baicalensis. Moreover, polyporenic acid C (PPAC), dehydrotumulosic acid (DTA), and tumulosic acid (TA) in Kai-Xin-San (KXS) were also identified as potent Aβ inhibitors. Further bioactivity validations indicated that these compounds could inhibit Aβ fibrillation, improve the viability in Aβ-induced PC-12 cells, and decrease the Aβ content and improve the behavioral ability in C. elegans. The molecular docking results confirmed that PPAC, DTA, and TA possessed good binding properties with Aβ. Collectively, the present study has provided a novel and effective HTS method for the identification of natural inhibitors on Aβ fibrillation, which may accelerate the process on anti-AD drugs discovery and development.
... Synaptic loss associated with Ab is also an early event in AD, and due to defects in synaptic plasticity, long-term potentiation and long-term depression of the synaptic strength are likely affected (53). Neurons in the entorhinal cortex that synthesize and innervate the hippocampus also die in AD (99). Entorhinal tau, not global tau, accumulation was correlated with hippocampal hyperactivation as shown among 15 MCI/AD patients given an item memory task during MRI scans (109). ...
Significance:
Alzheimer disease (AD) is an all-too-common condition in the aging population. However, aging does not automatically equal neurodegeneration and memory decline. Recent Advances: This review article involves metabolic changes in AD brain that are related to oxidative stress. Selected pathways are identified as potential targets for intervention in AD.
Critical issues:
One of the main factors of AD is the oxidative imbalance within the central nervous system causing a disruption in metabolic processes. Reactive oxygen species (ROS) are a natural consequence of many cellular processes, especially those associated with mitochondria, such as the electron transport chain. Some ROS, when kept under control and maintained at reasonable levels, often play roles in cell signaling. The cellular damage of ROS arises when oxidative imbalance occurs, in which case ROS are not controlled leading to a myriad of alterations in cellular metabolic processes. These altered pathways include, among others, dysfunctional glycolysis, calcium regulation, lipid metabolism, mitochondrial processes, and mTOR pathway dysregulation.
Future directions:
Understanding how ROS can lead to these alterations can, ideally, elucidate therapeutic options for retarding AD progression in the aging population.
... Central nervous system disorders have numerous pathological similarities at the subcellular and molecular levels, including oxidative stress, neuroinflammation, and memory impairment [7,8,[87][88][89]. All these processes increase in the aging brain [90]. ...
The number of patients with central nervous system disorders is increasing. Despite diligent laboratory and clinical research over the past 30 years, most pharmacologic options for the prevention and long-term treatment of central nervous system disorders and neurodegenerative disorders have been unsuccessful. Therefore, the development of drugs and/or functional foods to prevent the onset of neurodegenerative disorders is highly expected. Several reports have shown that polymethoxylated flavones (PMFs) derived from citrus fruit, such as nobiletin, tangeretin, and 3,3′,4′,5,6,7,8-heptamethoxyflavone, are promising molecules for the prevention of neurodegenerative and neurological disorders. In various animal models, PMFs have been shown to have a neuroprotective effect and improve cognitive dysfunction with regard to neurological disorders by exerting favorable effects against their pathological features, including oxidative stress, neuroinflammation, neurodegeneration, and synaptic dysfunction as well as its related mechanisms. In this review, we describe the profitable and ameliorating effects of citrus-derived PMFs on cognitive impairment and neural dysfunction in various rat and murine models or in several models of central nervous system disorders and identify their mechanisms of action.
... In Parkinson's and Alzheimer's disease, protein aggregation and mitochondrial dysfunction are two factors that promote oxidative stress, which is considered a major element in the evolution of these diseases [1]. In Parkinson's disease, at the level of substancia nigra pars compacta, α-synuclein aggregates (Lewy bodies) induce a degeneration of dopaminergic neurons involving oxidative stress [1]. ...
... In Parkinson's and Alzheimer's disease, protein aggregation and mitochondrial dysfunction are two factors that promote oxidative stress, which is considered a major element in the evolution of these diseases [1]. In Parkinson's disease, at the level of substancia nigra pars compacta, α-synuclein aggregates (Lewy bodies) induce a degeneration of dopaminergic neurons involving oxidative stress [1]. In Alzheimer's disease, the increase in oxidative stress mediated by β-amyloid protein aggregates (senile plaques) in the hippocampus and cortex promotes excitotoxicity (pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters) and synaptic degeneration leading to neurodegeneration [1]. ...
... In Parkinson's disease, at the level of substancia nigra pars compacta, α-synuclein aggregates (Lewy bodies) induce a degeneration of dopaminergic neurons involving oxidative stress [1]. In Alzheimer's disease, the increase in oxidative stress mediated by β-amyloid protein aggregates (senile plaques) in the hippocampus and cortex promotes excitotoxicity (pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters) and synaptic degeneration leading to neurodegeneration [1]. Identifying natural or synthetic molecules that could prevent oxidative stress is therefore a part of therapeutic strategies for treatment of Parkinson's and Alzheimer's diseases. ...
The brain, which is a cholesterol-rich organ, can be subject to oxidative stress in a variety of pathophysiological conditions, age-related diseases and some rare pathologies. This can lead to the formation of 7-ketocholesterol (7KC), a toxic derivative of cholesterol mainly produced by auto-oxidation. So, preventing the neuronal toxicity of 7KC is an important issue to avoid brain damage. As there are numerous data in favor of the prevention of neurodegeneration by the Mediterranean diet, this study aimed to evaluate the potential of a series of polyphenols (resveratrol, RSV; quercetin, QCT; and apigenin, API) as well as ω3 and ω9 unsaturated fatty acids (α-linolenic acid, ALA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA, and oleic acid, OA) widely present in this diet, to prevent 7KC (50 µM)-induced dysfunction of N2a neuronal cells. When polyphenols and fatty acids were used at non-toxic concentrations (polyphenols: ≤6.25 µM; fatty acids: ≤25 µM) as defined by the fluorescein diacetate assay, they greatly reduce 7KC-induced toxicity. The cytoprotective effects observed with polyphenols and fatty acids were comparable to those of α-tocopherol (400 µM) used as a reference. These polyphenols and fatty acids attenuate the overproduction of reactive oxygen species and the 7KC-induced drop in mitochondrial transmembrane potential (ΔΨm) measured by flow cytometry after dihydroethidium and DiOC6(3) staining, respectively. Moreover, the studied polyphenols and fatty acids reduced plasma membrane permeability considered as a criterion for cell death measured by flow cytometry after propidium iodide staining. Our data show that polyphenols (RSV, QCT and API) as well as ω3 and ω9 unsaturated fatty acids (ALA, EPA, DHA and OA) are potent cytoprotective agents against 7KC-induced neurotoxicity in N2a cells. Their cytoprotective effects could partly explain the benefits of the Mediterranean diet on human health, particularly in the prevention of neurodegenerative diseases.
Synucleinopathies are a group of neurodegenerative disorders characterized by pathologic aggregates of neural and glial α-synuclein (α-syn) in the form of Lewy bodies (LBs), Lewy neurites, and cytoplasmic inclusions in both neurons and glia. Two major classes of synucleinopathies are LB disease and multiple system atrophy. LB diseases include Parkinson’s disease (PD), PD with dementia, and dementia with LBs. All are increasing in prevalence. Effective diagnostics, disease-modifying therapies, and therapeutic monitoring are urgently needed. Diagnostics capable of differentiating LB diseases are based on signs and symptoms which might overlap. To date, no specific diagnostic test exists despite disease-specific pathologies. Diagnostics are aided by brain imaging and cerebrospinal fluid evaluations, but more accessible biomarkers remain in need. Mechanisms of α-syn evolution to pathologic oligomers and insoluble fibrils can provide one of a spectrum of biomarkers to link complex neural pathways to effective therapies. With these in mind, we review promising biomarkers linked to effective disease-modifying interventions.
Disruption of the gut‐brain axis in Parkinson's disease (PD) may lead to motor symptoms and PD pathogenesis. Recently, the neuroprotective potential of different PPARδ‐agonists has been shown. We aimed to reveal the effects of erucic acid, peroxisome proliferator‐activated receptors (PPARs)‐ligand in rotenone‐induced PD model in zebrafish, focusing on the gut‐brain axis. Adult zebrafish were exposed to rotenone and erucic acid for 30 days. LC‐MS/MS analysis was performed. Raw files were analyzed by Proteome Discoverer 2.4 software, peptide lists were searched against Danio rerio proteins. STRING database was used for protein annotations or interactions. Lipid peroxidation (LPO), nitric oxide (No), alkaline phosphatase, superoxide dismutase, glutathione S‐transferase (GST), acetylcholinesterase, and the expressions of PD‐related genes were determined. Immunohistochemical tyrosine hydroxylase (TH) staining was performed. LC‐MS/MS analyses allowed identification of over 2000 proteins in each sample. 2502 and 2707 proteins overlapped for intestine and brain. 196 and 243 significantly dysregulated proteins in the brain and intestines were found in rotenone groups. Erucic acid treatment corrected the changes in the expression of proteins associated with cytoskeletal organization, transport, and localization and improved locomotor activity, expressions of TH, PD‐related genes (lrrk2, park2, park7, pink1), and oxidant‐damage in brain and intestines in the rotenone group as evidenced by decreased LPO, No, and increased GST. Our results showed benefical effects of erucic acid as a PPARδ‐ligand in neurotoxin‐induced PD model in zebrafish. We believe our study, will shed light on the mechanism of the effects of PPARδ agonists and ω9‐fatty acids in the gut‐brain axis of PD.
