Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise

Abstract

The human brain is primarily composed of lipids, and their homeostasis is crucial to carry on normal neuronal functions. In order to provide an adequate amount of lipid transport in and out of the central nervous system, organisms need a set of proteins able to bind them. Therefore, alterations in the structure or function of lipid-binding proteins negatively affect brain homeostasis, as well as increase inflammation and oxidative stress with the consequent risk of neurodegeneration. In this regard, lifestyle changes seem to be protective against neurodegenerative processes. Nutraceutical supplementation with antioxidant molecules has proven to be useful in proving cognitive functions. Additionally, regular physical activity seems to protect neuronal vitality and increases antioxidant defenses. The aim of the present review was to investigate mechanisms that link lipid-binding protein dysfunction and oxidative stress to cognitive decline, also underlining the neuroprotective effects of diet and exercise.

Keywords: apolipoproteins; lipid-binding proteins; neurodegenerative disease; nutraceutical supplement; physical activity.

Figure 1

Lipid-binding proteins and oxidative stress in the pathogenesis of neurodegeneration. Oxidative stress is one of the main processes that modulate the LBPs functions. Indeed, when the production of ROS is predominant compared to antioxidant defenses activation, the apolipoproteins and FABPs activity are altered. Under these conditions, the ApoE ε4 mainly modulates the amyloidogenic process activation by the ERK1/2 MAP kinase pathway that induces the Aβ production in relation to AP-1-dependent APP transcription, and neuroinflammation, especially by promoting TNF-a, IL-1β, and IL-6 release. At the same time, FABP3 induces Aβ and a-syn accumulation and correlates with the alterations of cognitive performance, thus being considered an early predictor of cognitive decline. Similarly, under oxidative stress, FABP5 binds a-syn and affects the PPAR_γ pathway, thus leading to mitochondria dysfunctions. Moreover, FABP7 promotes lipid dysregulation by increasing the ω6/ω3 ratio, as well as induces the proinflammatory pathway activity, promoting NF-kB release. Overall, these processes contribute to defining the pathological mechanisms that conduct the neurodegeneration onset. The figure was created in BioRender.com, accessed on 18 September 2022.

Figure 2

Antioxidant supplementation in neurodegenerative diseases. Antioxidant supplementations exhibit beneficial effects on the onset and progression of neurodegenerative diseases. Vitamins E and C play an important role in reducing oxidative stress, while PUFAs exert positive effects on cell aging and cognitive performance. Coenzyme Q10 (2 weeks) is able to decrease brain oxidative stress and inflammation, improving levels of glutathione and superoxide dismutase (SOD). Regarding metals, zinc was demonstrated to improve cognitive functions (antioxidant capacity and BDNF release), while selenium regulates oxidative stress status and apoptosis (activities of AChE and caspase 3 decrease). Polyphenols can downregulate ROS levels, SOD, GPx, and CAT, and upregulate the expression of Nrf2, enhancing attention, executive (chlorogenic acids), and cognitive functions (curcuminoids) as well as reducing neuroinflammation in the AD brains (resveratrol). Active compounds in medicinal plants, such as thymoquinone, can counteract oxidative stress in the brains of rats exposed to head irradiation, affecting TSSA, NSSA, SOD, and PON activities. Probiotics exhibit antioxidant activity in CNS, improving some manifestations of neurodegenerative disorders. The figure was created in BioRender.com, accessed on 18 September 2022.

Figure 3

Neuroprotective effects of physical activity. Regular exercise is demonstrated to decrease oxidative stress and inflammation as well as increase the release of anti-inflammatory molecules, including IL-4 and IL-10. In addition, exercise triggers the PGC-1α/FNDC5 pathway in skeletal muscles, with the consequent release of Irisin, which is fundamental for the increase in neurotrophic factors. PA improves astrocyte functions with positive effects on hippocampal and vascular activities. In addition, exercise seems able to restore the AMPK and the JNK-BCL2 autophagy, preventing the accumulation of misfolded proteins and ensuring mitochondrial turnover. Exercise also acts on cell apoptosis and brain aging, restoring Wnt/β-Catenin signaling. Finally, PA enhances the release of dopamine improving brain functions in patients suffering from PD. The figure was created in BioRender.com, accessed on 18 September 2022.

Figure 4

Beneficial effects of nutraceuticals and exercise on lipid profile. Nutraceuticals and exercise are able to influence lipid profile and lipoproteins levels. A good lifestyle improves health and prevents possible chronic diseases. Nutraceuticals are provided by dietary sources, but they generally contain higher concentrations of bioactive compounds, exerting potential beneficial effects. The ω3 EPA and DHA were demonstrated to reduce VLDL hepatic synthesis and serum TG, while phytosterols impede intestinal cholesterol absorption, increasing LDL-C receptors and reducing LDL-C levels. Micronutrients are involved in regulating some apolipoproteins gene expression and affect HDL-C metabolism. Minerals such as magnesium and zinc and vitamins such as ascorbic acid and niacin impact lipoproteins and Apo-A1 levels. Polyphenols exert antioxidant activity against lipid peroxidation and promote hepatic LDL receptors. Soluble fibers encourage LDL-C decrease. In parallel, physical exercise promotes blood lipid consumption, reducing their levels, and induces lipid oxidation in skeletal muscle, giving the energy required during training. Moreover, in skeletal muscle, physical activity increases FABPpm content, especially in males. Exercise training induces LDL reduction and TG levels, especially when exercise intensity grows. The figure was created in BioRender.com, accessed on 18 September 2022.