Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential
Abstract
:1. Introduction
Lipid | Function in the Brain | Reference |
---|---|---|
TAGs | Not present in the brain | Hamilton et al., 2007; Tracey et al., 2018 [1,2] |
Sterol lipids | Precursor of sex hormones with protective effects in the CNS, such as the estrogens and testosterone | Liu et al., 2010 [12] |
Gives stability and rigidity to the cell membrane and can give thickness in certain areas, helping the formation of lipid rafts | Song et al., 2014 [13] | |
Sphingolipids | Membrane receptor for an extracellular GSL binding ligand, usually functioning as antigens or mediators of cell adhesion, and membrane GSLs interact laterally with other components of the cell membrane, particularly growth factor receptors | Lingwood et al., 2011; tracey et al., 2018 [2,11] |
Phospholipids and Fatty acids | Determine the fluidity of the membrane and have two tails of FAs | Song et al., 2014 [13] |
Determine the ubication of proteins across the membrane, and participate in the formation of lipid rafts | Carta et al., 2017 [15] | |
FAs can be used as an energy source | Panov et al., 2014 [4] | |
Can act as signaling molecules or as the precursors of signaling molecules, such as phospoinisitol-3 and ceramide | Carta et al., 2017; Kim et al., 2014 [15,27] |
2. Fatty Acid Roles in Non-Pathological Conditions
Palmitic Acid: Physiological Role in the Brain
3. Fatty Acid Accumulation, Lipotoxicity, and Brain Dysfunction
4. Pathways Involved in Palmitic Acid-Induced Toxicity
4.1. Role of Ceramides in Lipotoxic States
4.2. Inflammation Pathways (TLR, NF-κB, and Cytokines)
4.3. Lipotoxic Oxidative Stress
4.4. Endoplasmic Reticulum Stress Pathways
4.5. Apoptosis Related to PA
4.6. Autophagy and Palmitic Acid
5. Palmitic Acid and Neurogenerative Diseases
5.1. Alzheimer Disease
5.2. Parkinson’s Disease
5.3. Palmitic Acid and Other Neurodegenerative Disease
6. The Therapeutic Potential of Other Fatty Acid in NDs
6.1. Poly-Unsaturated Fatty Acids (PUFAs)
6.2. Linoleic Acid and Oleic Acid
6.3. Medium and Short Chain Fatty Acids
7. Conclusions and Further Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Reference | Species | Cell | Model | Concentration of PA (µM) and Time | Effects |
---|---|---|---|---|---|
Wong et al., 2014 [117] | R | Astrocytes Primary (P) | In vitro | 100 (24 h) | Observations included ROS formation in the mitochondria, mitochondrial membrane potential (MMP) collapse, and apoptosis, excluding the involvement of ER stress in PA toxicity. |
Ramirez et al., 2019 [116] | M | Astrocytes P | In vitro | 100 (24 h) | PA activated the Nrf2 pathway, reducing SOD activity and cell viability. |
Tu et al., 2019 [40] | M | Microglia BV-2 cells | In vitro-In vivo | 200 (4 h); HFD 60% (4 w) | Increases were observed in IL-6, IL-1 β, TNF-α, and COX2 expression and the ratio of phospho extracellular signal-regulated kinases (pERK)/ERK and a reduction of IkBα an Nf-kB inhibitor was observed. The same effects were seen in an animal model, plus the activation of microglia. |
Sergi et al., 2020 [43] | M | Neurons P | In vitro | 200 (6 h and 24 h) | PA induced the expression of IL-6 and TNF-α independent of TLR4 but, partially, via ceramide synthesis. |
Gupta et al., 2012 [91] | R | Astrocytes P | In vitro | 200 (18 h) | Astrocytes liberated IL-6 and TNF-α via TLR4 but not c-Jun N-terminal kinase (JNK) and TLR2. |
Hidalgo-Lanussa et al., 2018 [112] | M | Microglia BV-2 cells | In vitro | 250 (12 h) | PA increased ROS production and Nf-kB expression and also reduced MMP, cardiolipin, and cell viability. |
Liu and Chan, 2014 [118] | R | Astrocytes and neurons P | In vitro | 400 (24 h) | Activation of IPAF-ASC inflammasome in astrocytes led to the maturation of IL-1β, and neurons treated with the conditioned media of astrocytes with PA increased amyloid β42. |
Frago et al., 2017 [113] | R * | Astrocytes P | In vitro | 500 (24 h) | PA reduced the activation of ERK and Akt and the expression of IL10 and aromatase. PA also, augmented the activation of P38 mitogen-activated protein kinases, JNK, and the expression of IL-6. (C/EBP homologous protein (CHOP) and caspase 3are related to endoplasmic reticulum stress.) |
Gonzalez-Giraldo et al., 2019 [119] | H | Astrocytes t98 g cells | In vitro | 1000 (24 h) | PA increased IL6, TERT, TERC, DNMT3B, ESR1, and MIR155 genes and reduced CREB1, ALDH1L1, IL1B, and MIR125a. |
Gonzalez-Giraldo et al., 2018 [111] | H | Astrocytes t98 g cells | In vitro | 1000 (24 h) | PA reduced MMP, cardiolipin, and cell viability |
Yee-Wen et al., 2018 [120] | H | Astrocytes t98 g cells and Neurons SH-SY5Y | In vitro | 100–500 (24 h and 48 h) | PA induced apoptotic cell death in the SH-SY5Y and T98G cell lines, and treatment with similar concentrations of PA showed a much lower percentage of apoptosis in the T98G line, indicating that neurons are more susceptible to PA. These results were associated with increased lipid peroxidation and ROS production. |
Martin-Jimenez et al., 2020 [121] | H | Astrocytes, Normal Human Astrocytes primary | In vitro | 2000 (24) | Astrocytes treated with PA showeda reduction in cardiolipin and MMP and an increase in superoxide production, nuclear fragmentation, and cell death. |
Hsiao et al., 2014 [109] | H | Neurons SH-SY5Y | In vitro | 100–500 (24 h and 48 h) | Neuronal cell apoptosis, cell cycle G2/M arrest, beta-amyloid accumulation and the elevation of endothelial reticulum stress were observed. All of these effects were reversed by inhibiting protein palmitoylation. |
Ortiz-Rodriguez et al., 2018 [115] | M * pre-natal | Astrocytes P | In vitro | 250–500 (24 h) | PA reduced LC3-II, an autophagy marker, and incremented expression of CHOP, IL-6, and, only in males, TNF-α. Increased cell death was observed. |
Wang et al., 2012 [122] | M | Microglia P | In vitro | 25–200 (6 h and 24 h) | PA increased the expression of IL-6 and the TLR4-mediated activation of NF-kB, which was responsible for increases in TNF-a, IL-1b, and NO production. |
Yudkoff et al., 1989 [123] | R | Astrocytes P | In vitro | 360–720 (24 h) | PA reduced intracellular glutamine concentrations and increased leucine, isoleucine, and taurine. |
Park et al., 2011 [31] | M pre-natal | Neurons neural progenitor cells | In vitro | 50, 100, 200, and 400 (24 h) | PA was found to reduce NPC viability and proliferation by elevating intracellular OS. Furthermore, short-term PA-rich HFD impaired hippocampal neurogenesis by reducing the survival of newly generated cells and BDNF levels in the hippocampus. |
Ramirez et al., 2019 [116] | M | Astrocytes P | In vitro | 200 (2 h, 6 h, and 24 h); HFD 50% (8 w) | PA augmented ROS production and reduced SOD expression. In addition, in the animal model a reduction of BDNF was seen. |
Morselli et al., 2016 [124] | M * | Brain | In vivo | HFD 42% (16 w) | An HFD rich in SAFAs caused hypothalamic inflammation, principally in males, which was related to the decrease of PUFAs in the brain and the down regulation of PGC-1α/Erα. |
Douglass et al., 2017 [125] | M | Brain | In vivo | HFD 60% (8 w) | An HFD rich in SAFAs augmented hypothalamic inflammation and astrocytosis through the activation of Nf-kB and IKKβ. |
Blázquez et al., 2001 [126] | R | Astrocytes cortical | In vitro | 200 (24 h, 48 h, and 72 h) | PA induced apoptosis and involved the de novo synthesis of ceramide through the Raf-1/ERK pathway. |
Escartin et al., 2007 [127] | R | Astrocytes P | In vitro | 200 (24 h) | CNTF induced resistance to palmitic acid damage in activated astrocytes by increasing beta-oxidation. |
Patil et al., 2007 [32] | R | Astrocytes cortical | In vitro | 200 (24 h) | PA reduced GLUT1 expression, glucose uptake, and lactate release. |
Tracy et al., 2013 [128] | R | Microglia BV-2 cells | In vitro | 125 (24 h) | PA induced the activation of microglia, augmenting the mRNA levels of the proinflammatory cytokines Ia1β and IL-6. |
Yan et al., 2016 [129] | R | Retinal ganglional cells RGC-5 | In vitro | 100 (24 h) | Cell death due to ROS levels rose. |
Calvo-Ochoa et al., 2017 [130] | R | differentiated human neuroblastoma cells (MSN) | In vitro | 200 (24 h) | Inhibition of the insulin/PI3K/Akt pathway was observed. |
Buratta et al., 2008 [131] | H | Glioblastoma GL15 | In vitro | 600 (36 h) | PA generated a loss of cardiolipin, which was related to apoptosis via the release of cytochrome c and activation of caspase 3. |
Hernández-Cáceres et al., 2019 [22] | R | hypothalamic cell line N43/5 | In vitro | 100 (24 h) | PA activated (GPER40) and PA inhibited the autophagic flux and reduced insulin sensitivity. |
Portovedo et al., 2015 [132] | R | Brain | In vivo | HFD 35% 8–16 w | Intracerebroventricular injections of PA and HFD increased the expression of inflammatory markers and the downregulation of autophagic proteins. |
Reference | FA | FA Concentration and (Time) | Model | Cells | Disease Model | Effects |
---|---|---|---|---|---|---|
Tang et al., 2014 [214] | ARA | 50 µM (24 h) | M | Neurons PC12 | PD | A 50 µM concentration showed protection against MPP. However, 100 µM generated cytotoxicity. |
Marcheselli et al., 2003 [215] | DHA | 100–200 ng (24 h–48 h) | M | Brain | LP | DHA generated neuroprotection, inhibiting leukocyte infiltration, NF-κB, and cyclooxygenase-2. It also inhibited the signaling response to ischemia reperfusion. |
Descorbeth et al., 2018 [42] | DHA | 50 µM (48 h) | R | Schwann cells | LP | DHA reduced cell death generated by PA through the activation of the PI3K/AKT and mTORC2 kinase pathways. |
Meng et al., 2010 [216] | EPA | 0.8% (6 w) | M | Brain | PD | EPA reduced the pro-apoptotic Bax and caspase-3 mRNAs. |
Luchtman et al., 2012 [217] | EPA | 0.8% (6 w) | M | Brain | PD | EPA reduced memory deficit and the production of pro-inflammatory cytokines in the striatum. |
Luchtman et al., 2013 [218] | EPA | 50 µM (48 h) | H | neurons SH-SY5Y | PD | EPA downregulated ROS and nitric oxide. Besides, NADPH oxidase and COX-2 attenuated an increase in the Bax: Bcl-2 ratio, and cytochrome c release. However, EPA did not prevent a decrease in MMP. |
Tu et al., 2019 [40] | LA | 15–30 (1 h) | M | Microglia BV-12 | LP | LA reduced the expression IL-6, IL-1 β, TNF-α, COX2, reduced the ratio of pERK/ERK, inhibited IkBα and NF-κB, and reduced the activation of microglia. |
Moazedi et al., 2007 [219] | OA | 10% (4 w) | M | Brain | LP | Spatial learning and motor activity were significantly increased in rats fed with OA (10%) for 4 weeks compared to PA. |
Kwon et al., 2014 [150] | OA | 300 µM (24 h) | H | Neuron N2a | LP | OA pre-treatment attenuated PA-induced mitochondrial dysfunction and insulin resistance by inhibiting the phosphorylation of mitogen-activated protein kinase and the nuclear translocation of NF-κB p65. |
Sergi et al., 2020 [43] | OA | 125 µM (6 h) | M | mHypoE-N42 | LP | OA counteracted PA-induced intracellular ceramide accumulation, leading to a downregulation of IL-6 and TNF-α via ceramide synthesis, with OA and EPA being anti-inflammatory by decreasing PA-induced intracellular ceramide build-up. |
Govindarajan et al., 2011 [45] | NaB | 1.2 g/kg (6 w) | M | Brain | AD | Sodium butyrate (NaB) generated a recovery of memory function that was correlated with elevated hippocampal histone acetylation and increased the expression of genes implicated in associative learning. |
Ryu et al., 2003 [46] | NaB | 1–30 mM (24 h) | R | Neurons P | HD | NaB reduced neuron death induced by OS through the activation of Sp1. |
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Vesga-Jiménez, D.J.; Martin, C.; Barreto, G.E.; Aristizábal-Pachón, A.F.; Pinzón, A.; González, J. Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential. Int. J. Mol. Sci. 2022, 23, 2577. https://doi.org/10.3390/ijms23052577
Vesga-Jiménez DJ, Martin C, Barreto GE, Aristizábal-Pachón AF, Pinzón A, González J. Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential. International Journal of Molecular Sciences. 2022; 23(5):2577. https://doi.org/10.3390/ijms23052577
Chicago/Turabian StyleVesga-Jiménez, Diego Julián, Cynthia Martin, George E. Barreto, Andrés Felipe Aristizábal-Pachón, Andrés Pinzón, and Janneth González. 2022. "Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential" International Journal of Molecular Sciences 23, no. 5: 2577. https://doi.org/10.3390/ijms23052577