Dietary Lipid Intervention in the Prevention of Brain Aging

Wei Xiong; Bing Fang; Xiaoyu Wang; Ming Zhang; Min Du; Jiazeng Sun; Juan Chen; Yixuan Li; Changhao Sun; Xingen Lei; Xue Zhang; Fazheng Ren

doi:10.1016/j.eng.2023.04.012

Engineering ›› 2024, Vol. 37 ›› Issue (6) :140 -150. DOI: 10.1016/j.eng.2023.04.012

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Dietary Lipid Intervention in the Prevention of Brain Aging

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Abstract

As people live longer, the burden of aging-related brain diseases, especially dementia, is increasing. Brain aging increases the risk of cognitive impairment, which manifests as a progressive loss of neuron function caused by the impairment of synaptic plasticity via disrupting lipid homeostasis. Therefore, supplemental dietary lipids have the potential to prevent brain aging. This review summarizes the important roles of dietary lipids in brain function from both structure and mechanism perspectives. Epidemiological and animal studies have provided evidence of the functions of polyunsaturated fatty acids (PUFAs) in brain health. The results of interventions indicate that phospholipids—including phosphatidylcholine, phosphatidylserine, and plasmalogen—are efficient in alleviating cognitive impairment during aging, with plasmalogen exhibiting higher efficacy than phosphatidylserine. Plasmalogen is a recognized nutrient used in clinical trials due to its special vinyl ether bonds and abundance in the postsynaptic membrane of neurons. Future research should determine the dose-dependent effects of plasmalogen in alleviating brain-aging diseases and should develop extraction and storage procedures for its clinical application.

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Brain aging / Nutritional intervention / Phospholipids / Phosphatidylcholine / Phosphatidylserine / Plasmalogen

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Wei Xiong, Bing Fang, Xiaoyu Wang, Ming Zhang, Min Du, Jiazeng Sun, Juan Chen, Yixuan Li, Changhao Sun, Xingen Lei, Xue Zhang, Fazheng Ren. Dietary Lipid Intervention in the Prevention of Brain Aging. Engineering, 2024, 37(6): 140-150 DOI:10.1016/j.eng.2023.04.012

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1. Introduction

There are 264 million people in China aged 60 years or more, accounting for 18.7% of the total population, and the proportion of China’s elderly population continues to increase with improvements in the economy and medical care [1]. Disorders in older people (over 60 years) comprise 23% of global medical expenses [2], and neurological disorders are the leading causes of disability and mortality in seniors [3]. In 2018, dementia prevalence in China was 5.30% for individuals aged 60 years or older [4], accounting for approximately 25% of the entire population with dementia worldwide [5]. Moreover, 60%-70% of dementia cases are due to Alzheimer’s disease (AD) [6]. In China, AD-associated costs account for 1.47% of the gross domestic product (GDP), whereas worldwide AD costs account for 1.09% of the global GDP, indicating that the socioeconomic costs of AD in China are greater than the worldwide average [7]. Age-related neurodegenerative diseases are major social and economic problems presented by an aging society.

To address this issue, the Chinese Academy of Sciences has proposed the China Brain Project, which aims to explore the neural mechanisms underlying the cognition changes in, diagnosis of, and interventions for brain diseases. In addition, International Life Sciences Institute Europe has launched the Nutrition for the Ageing Brain project to collect evidence supporting the impact of nutrients on brain health, in the hope of formulating precise nutritional intervention for the aging brain. Although there is a wealth of data suggesting the beneficial effects of specific nutritional intervention on cognitive function and brain health, the therapeutic mechanisms are not fully understood, and the pharmacological potential of these nutrients and bioactive compounds must be further assessed.

Brain aging is characterized by a progressive decline in neuronal function that eventually contributes to the progress of mild cognitive impairment (MCI), AD, and other forms of dementia [8]. Thus, preventing the decline of neuronal function could delay brain aging and the consequent age-related neurodegenerative diseases. Lipids—especially phospholipids—are the main component of neuronal membranes and are necessary for the structure and function of neurons in the brain. Micronutrients such as vitamins and minerals are also important for the maintenance of brain function. Insufficiency of these nutrients leads to brain dysfunction [9], [10]. This review discusses the roles of dietary lipids in the prevention of brain aging, together with intervention methods and underlying mechanisms.

2. Mechanisms of brain aging

2.1. Synaptic plasticity and brain aging

The functional units of the brain are neurons, which send electrochemical signals to one another, performing the complex and essential functions of the brain. For proper function, neurons must be able to communicate with each other through synapses. A chemical synapse consists of a synaptic cleft, presynaptic membrane, and postsynaptic membrane [11]. During synaptic transmission, neurotransmitters are released into the synaptic cleft after vesicle fusion with the presynaptic membrane. Then, neurotransmitters bind to receptors on the dendritic spine microdomains of the postsynaptic membrane and transmit neural signals into the postsynaptic neuron [11].

Cognitive impairment, which is a feature of AD and brain aging, is largely due to an imbalance in the cellular and molecular mechanisms of synaptic plasticity [12] (Fig. 1). Synaptic plasticity refers to the activity-dependent change in the strength and efficiency of synaptic transmission at preexisting synapses, which has long been proposed to play a critical role in learning and memory [12], [13]. In aging animals, changes in the number and function of synapses appear in different brain regions, such as the striatum, cerebellum, and hypothalamus. These changes affect motor coordination, locomotor coordination, and endocrinology, respectively [14], [15], [16]. However, the most significant changes in synapse number and function occur in the hippocampus and prefrontal cortex, which are associated with impaired learning and memory functions [17], [18]. In addition, aging animals have a higher threshold for long-term potentiation induction and a lower threshold for long-term depression induction compared with young animals [18], [19].

Synaptic plasticity is associated with structural synaptic changes, such as changes in the structural features of the existing dendrites, density and distribution of spines, and stabilization of new synaptic contacts. During aging, the density of spines is reduced in the cornu ammonis (CA)3 region and dentate gyrus, but is not altered in the CA1 region of the hippocampus [20]. Spines are the major sites for excitatory synapses, and a decrease in their number could reflect a decline in synaptic densities [21]. Aged animals have lower postsynaptic density in the CA1 neurons in their hippocampus, which is the site of many key proteins involved in signaling and plasticity [20], [22]. With age, dendritic tree length and complexity have been shown to increase in the CA1 region of the hippocampus and decrease in the prefrontal cortex [20].

A series of neural activities—including the activation of neurotransmitters, kinase systems and adenosine triphosphatase (ATPase), the influx of Ca²⁺, the induction of gene expression and translation, and the regulation of proteins—are essential in establishing the plastic changes underlying memory [11], [13]. The efficiency of these activities is affected by the functional proteins on the synaptic membrane [23]. For example, the glutamatergic system controls the influx of Ca²⁺ to neurons through N-methyl-D-aspartic acid (NMDA) reporters on the synaptic membrane. The density of NMDA receptors decreases with age, as does the density of metabotropic glutamate receptor subtypes 3 and 5 [24], [25]. The magnitude and duration of intracellular Ca²⁺ changes affect synapse plasticity by regulating synaptic transmission and mediating dendrite growth and retraction in the postsynaptic membrane [26], [27].

2.2. The importance of lipid homeostasis in synaptic plasticity

Synapses are enriched with various lipid species, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and sphingolipids, along with other less abundant components such as cholesterol and phosphoinositide [28], [29]. This unique lipid composition is important for the structure and function of synapses. For example, changes in lipid composition determine the viscosity and fluidity of the membrane, thereby controlling the mobility and lateral diffusion of membrane molecules [28]. The composition of lipid bilayers affects the spatial organization of membrane lipids and associated proteins [30]. In addition, lipids can influence the location or activation of crucial synaptic protein complexes [31]. Overall, considering the importance of lipids in the structure and function of the synaptic membrane, as well as the connections between the synaptic membrane and synaptic plasticity, it can be reasoned that lipid homeostasis is important to synaptic plasticity and normal brain function.

The brain is rich in lipids [32], which increase during the first 20 years of human life and then begin to decrease gradually after the age of 50 [33]. Lipid dysregulation is thought to underlie several cognitive disorders [34], [35]. It has been reported that the contents of docosahexaenoic acid (DHA) and arachidonic acid (ARA) in the gray matter of the orbitofrontal cortex decrease significantly during aging [36]. Phospholipids are the major components of membranes, and the disorganization of lipid components during aging may affect membrane fluidity, leading to impairment of neurotransmitter transport, release, and reception [37]. The components of triglyceride, PC, PE, PS, sphingomyelins, and sterols are altered in AD or the aging brain, and these changes may contribute to alterations in membrane fluidity and integrity [38], [39], [40], [41], [42]. Subtle changes in lipid composition could affect brain functions, including structural development, nerve-impulse transmission, neurogenesis, synaptogenesis, and myelin formation [32], [43]. Because lipids are mainly absorbed through the diet, dietary lipid supplementation is a promising intervention for the prevention of brain aging-related diseases.

3. Polyunsaturated fatty acids (PUFAs) and brain function

Brain aging is often accompanied by malnutrition. Supplementation of n-3 PUFAs, PS, vitamin B complexes, and flavonoids—whether individually or in combination—slows brain atrophy and cognitive decline, and reduces the risk of age-related neurodegenerative diseases [44]. Lower vitamin B₁ and B₁₂ levels have been associated with a higher risk of brain tissue loss [9], [10], and vitamin C reduces the formation and aggregation of amyloid-β (Aβ) in both humans and mice with AD [45], [46]. Interestingly, flavonoids can alleviate AD-induced neuronal death [47]. Among these supplements, PUFAs are the lipid components of primary concern for improving brain function.

3.1. PUFAs are important for brain function

DHA and eicosapentaenoic acid (EPA) are the most abundant n-3 PUFAs, and ARA is the most abundant n-6 PUFA in the brain [48]. Interestingly, for a specific region, the abundance of PUFAs is negatively correlated with the presence of monounsaturated fatty acids [48]. In fact, only a small fraction of fatty acids act as signaling molecules or as substrates for post-translational modifications. Most fatty acids—especially n-3 PUFA—are incorporated into membrane lipids as their acyl chains, affecting the composition, structure, and function of membrane proteins [49], [50]. This is the most important function of fatty acids in the brain. The composition of neuronal membrane fatty acids regulates the physical properties and biological activity of the membrane, which is important for efficient synapse transmission [51], [52]. In addition, the unsaturation level of mitochondrial inner-membrane fatty acids may affect ATP synthesis and the production of reactive oxygen species (ROS) by dictating the rate of electron transport chain flux [51].

The high levels of unsaturation of EPA and DHA endow them with the ability to affect membrane fluidity, which is necessary for synaptic plasticity [53]. n-3 PUFAs also regulate signal transduction via recruiting membrane-bound enzymes (Na/K-dependent ATPase) and regulating protein kinase C activity [54], [55]. Moreover, DHA has been shown to have antioxidant properties, which may help protect the brain from degeneration [56]. Aside from the amount of PUFAs, the ratio of n-6 PUFAs to n-3 PUFAs is important, as it affects the balance of their derived eicosanoids in the body [57,58].

3.2. Effect of PUFAs supplementation on cognition function

The beneficial effects of PUFAs on brain function have been widely studied (Table 1 [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70]). There is a strong correlation between the plasma n-3 PUFAs levels and cognitive function, and intervention with n-3 PUFAs (2.3 g·d⁻¹) has been shown to slow cognitive deterioration in AD patients [59]. Higher plasma EPA or DHA concentration is associated with less atrophy in the hippocampus and amygdala, as well as a lower incidence of AD [71], [72]. In addition, the benefits of PUFA supplementation in cognition and memory have been observed in healthy individuals [60], [61], [62], [63].

The abundance of DHA, one of the widely studied n-3 PUFAs, is closely associated with brain function [73], [74], and supplementation with DHA (2 g·d⁻¹) was shown to improve the cognitive function of MCI patients [64]. As a component of the membrane, DHA regulates membrane fluidity, which further affects the formation and differentiation of novel neurites and synapses, the refinement of synaptic connectivity, neurotransmitter release, and memory-consolidation processes [73], [75], [76]. DHA supplementation can enhance spontaneous glutamatergic synaptic activity and promote the expression of NMDA receptor in primary neurons [77]. Recently, DHA was also found to protect neuronal membrane lipid peroxidation through the activation of glutathione peroxidase 4 [78]. These findings show that n-3 PUFAs—especially DHA—may be beneficial for alleviating cognitive impairment, as well as brain disorders caused by aging.

However, dietary DHA supplementation is not always effective, especially in the elderly. For example, an intervention with n-3 PUFAs (DHA 800 mg·d⁻¹ + EPA 225 mg·d⁻¹) in a multidomain AD preventive trial did not improve cognition in patients with MCI and mild AD [65], and negative effects of n-3 PUFAs were reported in healthy older and cognitively impaired individuals [66], [67], [68], [69], [70]. These null reports might be attributed to the poor absorption and low efficiency of DHA in crossing the blood-brain barrier [79].

3.3. Active forms of PUFAs in the brain

Phospholipids have large quantities of PUFAs in their sn-1 and sn-2 chains, and an imbalance of n-3/n-6 PUFAs ratios in phospholipids is associated with depression and retinopathy [80], [81]. DHA is the most enriched PUFA in the brain, especially in synaptic membranes, which contain 32%-40% DHA-containing phospholipids [82]. It was found that the benefits of DHA in brain function are due to the increased enrichment of DHA-phospholipid. Moreover, supplementation of DHA in the form of phospholipids is more effective than its supplementation in the form of free fatty acids or triglycerides, regardless of whether in terms of increasing brain DHA levels or improving memory function [83], [84], [85], [86]. The possible mechanism for this efficiency differentiation can be explained as follows: Dietary DHA in fatty acid or triglyceride form is digested by pancreatic enzymes, resulting in the formation of unesterified free acids that are incorporated into chylomicron primarily as triglycerides. However, dietary DHA in phospholipid form is digested by phospholipase A2 to form lysophospholipids, which are incorporated into chylomicron or high-density lipoprotein. Furthermore, the blood-brain barrier preferentially takes up DHA in the form of lysophospholipids to effectively enrich the brain [83]. Therefore, intervention with phospholipids is more efficient than PUFAs in improving brain function [87], [88].

4. Phospholipids in brain aging

4.1. Composition of phospholipids in the brain

Phospholipids account for more than 60% of the total membrane lipids of neurons [43], [89]. Phospholipids have similar structure, with two fatty acids attached to the sn-1 and sn-2 positions and a varying phosphate headgroup at the sn-3 position of the glycerol backbone (Fig. 2). Based on the headgroup at the sn-3 position, phospholipids are mainly divided into PC, PE, PS, phosphatidylinositol, phosphatidic acid, and cardiolipin [88] (Fig. 2(a)). PE is the most abundant phospholipid in the mammalian brain [87]. Furthermore, synaptic microdomains exhibit different phospholipid compositions: PS is enriched in vesicle membranes, while PE and PC are enriched in peri-synaptic densities and lipid rafts of the postsynaptic membrane, respectively [38], [90] (Fig. 3(a)). Dynamic phospholipid remodeling allows for the rapid changes in membrane morphology required for synaptic transmission, implying that maintaining a critical phospholipid composition is necessary for the integrity of the synaptic structure [38], [91].

4.2. Changes of phospholipids in brain dysfunction

It has been reported that the PC contents are significantly altered in the plasma of AD patients [92]. PC concentrations—especially unsaturated PC, including PC 36:5, PC 38:6, and PC 40:6—are lower in individuals diagnosed with AD and the elderly, and this decline may be associated with atrophy of the hippocampus [41], [92], [93]. Moreover, aggregation of plasmanyl-PC (16:0/2:0) is related to the hyperphosphorylation of tau and neuron loss [38].

PS is essential for the proper functioning of neuronal membranes, myelin, and especially synapses. DHA-PS accounts for more than 80% of the PS in gray matter [94], and a reduction in DHA-PS has been shown to be associated with impaired brain function [39], [95]. Decreased levels of DHA-PS were found in senescence-accelerated mice, which had a shorter life span, cognitive impairment, and an increase in hippocampal Aβ-peptide content [95]. Similar results were found in AD patients [39].

PE mainly exists as plasmenyl-PE (often referred to plasmalogen) and diacyl-PE (Fig. 2(b)). Plasmalogens are characterized by the presence of a vinyl ether bonds at the sn-1 position, which has a phosphate head group that is 95% or higher ethanolamine with small amounts of choline [96], [97]. Plasmalogen content has been found to increase gradually until the age of 40, and then begin to decline significantly by the age of 70 [98]. Furthermore, the brain level of plasmalogen (18:0/22:6), rather than diacyl-PE (18:0/22:6), has been associated with declined cognition [99]. Deficiencies in plasmalogen have been widely found in patients with early AD [100], Parkinson’s disease (PD) [101], schizophrenia [102], and rhizomelic chondrodysplasia punctata [103]. In addition, both human and animal studies indicate that plasmalogen deficiency is an etiological factor of AD and dementia [104]. Furthermore, in response to oxidative stress, the contents of plasmalogen decrease, whereas those of diacyl-PE remain unchanged, indicating that plasmalogens may protect the organism from oxidative stress by being oxidized themselves [105].

5. Phospholipids intervention for brain aging

Phospholipids are beneficial for brain function, including cognition [87]. A phospholipid-rich diet for four months prevented memory decline in aging mice by improving vascular density and synaptic plasticity [106]. Bovine milk-derived phospholipids have been shown to improve cognitive performance in high-perfectionist men [107]. Phospholipid species have different intervention effects on brain aging. Selected studies evaluating the effects of PC, PS, and plasmalogen on aging-related brain diseases are summarized in Table 2 [101], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116] and Figs. 3(b)-(d).

5.1. PC

Dietary PC—the precursor of acetylcholine—can be used for improving cognitive impairment by activating cholinergic neurons in the hippocampus and prefrontal cortex [117], [118]. Supplementation with PC in mice increased plasma DHA and ARA levels, learning ability [118], and spatial memory [119]. Although PC has the potential to improve memory degeneration, more evidence is needed on the effect of PC on memory enhancement in AD patients or older adults with cognitive decline.

5.2. PS

PS is enriched in the presynaptic membrane and is involved in neurotransmitter release, which relies on presynaptic membrane depolarization and Ca²⁺ influx. Improving the PS level can increase the fluidity of the neuronal membrane and consequently increase the activity of ATPase to facilitate inter-neuronal communication [120], [121]. The treatment of aged mice with PS was shown to increase the density of NMDA receptors to enhance long-term potentiation [121]. PS supplementation can also slow the rate of loss of dendritic connections by prolonging the maintenance of pyramidal dendritic spine density [122]. Moreover, PS can protect neuron membranes from oxidative damage [123] and can active cholinergic neurons by increasing the release of acetylcholine in the brain, which is an effective treatment for AD [108]. The effectiveness of dietary PS in reducing the risk of dementia in the elderly has been assessed by the US Food and Drug Administration (FDA) [124]. Supplementation with PS (100-300 mg·d⁻¹) can efficiently slow or reverse structural and biochemical changes during brain aging, which increases immediate and delayed verbal recall, and can also prevent cognitive decline in elderly people with memory complaints or patients with dementia [108], [109], [110], [111], [112]. This is particularly the case for DHA-containing PS [113], [114]. PS is also effective in enhancing locomotor performance; however, its effect on locomotor impairment due to aging remains to be investigated [125].

Most of the PS used for nutritional interventions is derived from soybeans, being obtained from serine and soybean-derived PC catalyzed by phospholipase D [126]. In the brain, PS is synthesized from the replacement of ethanolamine of PE with serine, which is catalyzed by phosphatidylserine synthases 2, or from the replacement of the choline of PC with serine, which is catalyzed by phosphatidylserine synthases 1 [94]. Moreover, brain PS preferentially uses DHA phospholipids [94]. According to the FDA report, 62% of the total fatty acid content of soybean-derived PS is linoleic acid (C18:2), along with oleic acid (C18:1, 15%), palmitic acid (C16:0, 14%), α-linolenic acid (C18:3, 5%), and stearic acid (C18:0, 4%); DHA is not present [127]. This report implies that oral soybean-derived PS may only provide serine and phospholipid backbones for brain PS synthesis, which may account for the high levels (100-300 mg·d⁻¹) of soybean-derived PS supplementation required.

5.3. PE

Interventions with PE have mainly focused on plasmenyl-PE, also known as plasmalogen. Plasmalogen is enriched in the peri-synaptic areas of the postsynaptic membrane and is involved in several brain functions, including vesicle fusion, membrane raft composition, endoplasmic reticulum stress, transmembrane protein function, and cholesterol transport, which are important for synaptic plasticity [128], [129], [130]. It can also act as a scavenger of reactive oxygen/nitrogen species and may participate in lipid peroxidation [129], [130]. In addition, plasmalogen has been suggested to play a key role in anti-neuroinflammation by inhibiting the endocytosis of toll-like receptor 4 [131]. Moreover, it can be used as a substrate for PS synthesis via base-exchange reactions [132]. Animal experiments showed that oral administration with plasmalogen was better than diacyl-PE administration in cortical plasmalogen (18:0/22:6) enrichment and in improving learning abilities in cognitive-deficient rats [133]. Similar results were found in an in vitro experiment [134]. In humans, the oral administration of plasmalogen (1 mg·d⁻¹) improved cognitive parameters in females under 77 years old with mild AD [115] and dose-dependently improved verbal and visual memory in mild forgetfulness volunteers [116]. The beneficial effect of plasmalogen on the brain has also been observed in PD patients, increasing the plasma and erythrocyte plasmalogens to almost normal levels and concomitantly improving some clinical symptoms, including daily activity, social support, cognition, and bodily discomfort [101]. Furthermore, the precursor molecules of plasmalogen—namely, 1-O-octadecyl-sn-glycerol (OG) and an alkyl-diacyl plasmalogen precursor with DHA at the sn-2 position (PPI-1011)—have been shown to improve the symptoms of rhizomelic chondrodysplasia punctata and PD, respectively, by increasing plasmalogen levels [135], [136].

The plasmalogen used for nutritional interventions is usually derived from scallops and contains a high content of n-3 PUFAs. Due to plasmalogen’s specific vinyl ether bonds at the sn-1 position and its abundance in the peri-synaptic densities of the postsynaptic membrane, the effective dose of plasmalogen (1 mg·d⁻¹) was found to be much lower than that of PS (100 mg·d⁻¹) in clinical trials to improve brain function during aging. However, animal experiments exhibited some inconsistency in terms of the effective dose, which may be due to the different methods of administration [137], [138]. Plasmalogen is usually given through oral gavage in animal studies, which exposes the plasmalogen directly to the stomach. However, the vinyl ether bond of plasmalogen is unstable under acidic conditions, and most plasmalogen will degrade into aldehydes in the stomach [139]. This may be the reason why higher doses are required in animal experiments. The use of enteric capsules for oral insulin prevents the effects of the gastric acid environment on the structure and efficacy of insulin [140]. Thus, microencapsulation and target delivery may improve the utilization of plasmalogen.

6. Conclusions

Neurological disorders are one of the greatest global challenges, making it increasingly important to develop nutritional intervention that can improve brain function during aging. Lipids in the brain have complex structural and functional diversity and play an essential role in intracellular and intercellular signaling. Clinical and mechanistic analyses suggest that PS and plasmalogen (plasmenyl-PE) may have better intervention effects than PUFAs in terms of cognitive impairment and brain aging by maintaining lipid homeostasis. The PS used in nutritional interventions has low contents of DHA and other n-3 PUFAs, while plasmalogen usually contains high levels of n-3 PUFAs. Due to the specific vinyl ether bonds in its structure and its abundance in the postsynaptic membrane, plasmalogen may be more effective than PS in improving brain function during aging. The clinical effectiveness of precursor molecules of plasmalogen also demonstrates plasmalogen’s importance. However, despite its noteworthy function, plasmalogen has inadequate application, due to its acid intolerance and easily oxidized vinyl ether bonds, inconsistent effective doses in clinical trials and animal studies, and other unclear mechanisms. In conclusion, dietary phospholipid may be the most promising substance for alleviating brain aging, but more studies are still needed for exploring the digestion and metabolism pathway, as well as the bioavailability. Plasmalogen may be one of the most promising phospholipids for brain protection, and further studies are required to focus on its underlying mechanism and practical application.

Acknowledgments

The work was supported by the National Key Research and Development Program of China (2022YFD2101003) and the 111 Project from the Ministry of Education of the People's Republic of China (B18053).

Compliance with ethics guidelines

Wei Xiong, Bing Fang, Xiaoyu Wang, Ming Zhang, Min Du, Jiazeng Sun, Juan Chen, Yixuan Li, Changhao Sun, Xingen Lei, Xue Zhang, and Fazheng Ren declare that they have no conflict of interest or financial conflicts to disclose.

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