Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential

Abstract

One of the most common lipids in the human body is palmitic acid (PA), a saturated fatty acid with essential functions in brain cells. PA is used by cells as an energy source, besides being a precursor of signaling molecules and protein tilting across the membrane. Although PA plays physiological functions in the brain, its excessive accumulation leads to detrimental effects on brain cells, causing lipotoxicity. This mechanism involves the activation of toll-like receptors (TLR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, with the consequent release of pro-inflammatory cytokines, increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy impairment. Importantly, some of the cellular changes induced by PA lead to an augmented susceptibility to the development of Alzheimer’s and Parkinson´s diseases. Considering the complexity of the response to PA and the intrinsic differences of the brain, in this review, we provide an overview of the molecular and cellular effects of PA on different brain cells and their possible relationships with neurodegenerative diseases (NDs). Furthermore, we propose the use of other fatty acids, such as oleic acid or linoleic acid, as potential therapeutic approaches against NDs, as these fatty acids can counteract PA’s negative effects on cells.

Effects of Thymoquinone (TQ) on the Molecular Structure and Total Antioxidant Capacity of Cerebellum Tissue of Healthy Rats

“…A significant increase in unsaturated lipid content in the 10 mg/kg TQ group compared to the control group was observed in the present study. The study showed that unsaturated fatty acids decrease inflammatory responses, saturated fatty acid-induced cytotoxicity, and ROS production in various models of brain damage and neurodegenerative diseases (29). Moreover, total antioxidant capacity of cerebellum tissues of rats treated with 10 mg/kg TQ was significantly increased when compared with the control according to the present study's results.…”

Rethinking of Alzheimer's disease: Lysosomal overloading and dietary therapy

“…Disorder of lipid metabolism, especially when the palmitic acid (PA) accumulates, would cause lipid-overload lipotoxicity and inhibit the autophagic flux in neurons, which is the whole autophagic process from the synthesis of the autophagosomes to their lysosomal fusion and degradation (Fang et al, 2020 ; Hernández-Cáceres et al, 2020 ; Chung, 2021 ; Vesga-Jiménez et al, 2022 ). PA induces APP palmitoylation and enhances Aβ accumulation via proteolytic processing of APP by multiple enzymes, such as BACE1, β-secretase, and γ-secretase (Kim et al, 2017 ; Zareba-Kozioł et al, 2018 ).…”

“…And in Sirt3 -silenced mouse brain-derived endothelial cells, the neuro-inflammatory response was exacerbated (Tyagi et al, 2021 ). Many researchers proposed the use of unsaturated fatty acids (UFA), such as oleic acid (OA) or linoleic acid (LA), as a potential therapeutic approach against AD, because that these UFA could counteract PA's detrimental effects on cells (Piomelli, 2013 ; Vesga-Jiménez et al, 2022 ). For example, oleic acid ingestion stimulates oleoylethanolamide mobilization into the mucosal cells of the gut, which triggers a peroxisome proliferator-activated receptor (PPAR)-mediated signals that travel through the afferent vagus nerve to the hypothalamus, augmenting satiety and showing beneficial effects to the nervous system (Piomelli, 2013 ).…”

Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?

“…PA is the most common SFA, accounting for 20–30% of the total fatty acids in the human body. It has been considered detrimental to the health because it causes lipotoxicity [ 104 ], although its negative effects may be related to an imbalance of dietary PA/PUFAs [ 105 ]. PA appears to inhibit the proliferation of mouse-derived NPCs and favor astrogliogenesis, an effect associated with the activation of Stat3 (a transcription factor that promotes astrogliogenesis) [ 106 ].…”