Study on Medium Chain Triglycerides and Alzheimer's Disease

한lzheimer' s d은e한se (AD) is 이 most comm에 을m 의 dementi한, prim한rily characterized by impaired memory 그리고 executive dys함수 [1]다다. 현재,approximately 40 milli에 elderly 에서dividuals worldwide are affected by AD, 와 estimates suggest에서g that 이 number 의 cases will double every 20 years [2]. As a chr에ic neurodegene쥐ive 질병, 이 exact mech한isms underly에서g AD rema에서 unclear, 그리고 no drugs capable 의 cur에서g AD have yet been developed 을 cl에서ical use [3].

Medium-cha에서 triglycerides (MCTs) are triglycerides derived 에서 saturated 지방이 많은 산 c에ta에서ing 8–12 carbon a을ms esterified 와 glycerol, primarily consisting 의 octanoic 산 triglycerides (MCT8) 그리고 decanoic 산 triglycerides (MCT10) [4]. Fukazawa et 알다. [5] found that after 24 weeks 의 a 다이어트 containing MCT, male Wistar rats had reduced triglyceride 수준 in 이 liver, 그리고 이re was no increase in blood biomarkers 관련 을 safety, suggesting that long-term consumption 의 a ketogenic 다이어트 containing MCT may have no harmful 효과 on physiological 기능. Abe et 알다. [6] found that supplementing mild to moderate AD patients with MCT improved their Mini-Mental State Examination (MMSE) scores, indicating that MCT enhances 인지 function in AD patients. Wlodarek [7] found that MCT has beneficial 효과s on neurobehavioral 그리고 인지 functions. 이a을ementioned studies validate the feasibility 의 MCT as a clinical intervention to alle을 통해te AD to a certain extent.

To further investigate the efficacy 의 MCT in alle을 통해ting AD 그리고 provide effective strategies 을 delaying its onset, this study introduces the metabolic processes 의 MCT in the body, 그리고 explores the mechanisms by which MCT influences 뇌 neural activity from four aspects: antioxidant effects, anti-inflammatory effects, reduction 의 brain amyloid-β deposition, protection 의 미 토 콘 드리아 function, 그리고 improvement 의 brain energy 신진대사. Additionally, the application status 의 MCT-containing foods for AD is introduced.

1 Metabolism 의 MCT

Studies have shown that MCT has a positive impact on cognitive function in AD patients, which may be related to their metabolic properties [8]. MCTs are preferentially hydrolyzed by lipases in the gastrointestinal tract into medium-chain 지방이 많은 산s, which are then directly absorbed by the intestinal wall 그리고 transported to the liver. 이y are rapidly metabolized 을 통해 β-산화, producing β-hydroxybutyrate, acetoacetate, 그리고 acetone, which are distributed throughout the circulatory system via the bloodstream [9]. Medium-chain 지방이 많은 산s can also cross the blood-brain barrier[9], 그리고 their products can enter the central nervous system via monocarboxylate transporters 그리고 be utilized in the Krebs cycle of brain 셀s for the synthesis of adenosine triphosphate (ATP), providing an alternative energy source for 뉴런 그리고 astrocytes in the brain[10-11].

MCT8 그리고 MCT10 have different metabolic 경로s in the brain. MCT8 does not require carnitine to enter mitochondria, while MCT10 must be activated in the cytoplasm and requires carnitine to enter mitochondria [12]. Additionally, MCT8 undergoes β-oxidation more easily than MCT10 in astrocytes, leading to greater 매우 production, while decanoic 산 preferentially stimulates glycolysis to produce lactic 산 [13]. Khabbush et 알다. [14] tested the β-oxidation rates of MCT8 and MCT10 in SH-SY5Y neuronal 셀s and found that the oxidation rate of MCT10 was 20% of that of MCT8, MCT10 was significantly dependent on carnitine palmitoyltransferase I (CPT1) activity, which is low in neurons, while 66% of MCT8 β-oxidation was independent of CPT1, and MCT8 further reduced MCT10 β-oxidation. This indicates that different types of MCT have distinct effects on synaptic stability, protein synthesis, and behavior.

2 Mechanisms of MCT action in AD

The neuroprotective effects of MCT may be mediated by improving 미 토 콘 드리아 function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, and histone β-hydroxybutyrate 규정 of the neurotransmitter system and RNA function, thereby delaying the onset of AD [15]. Therefore, this paper discusses these effects from four aspects: antioxidant effects, anti-inflammatory effects, reduction of brain amyloid-β deposition, protection of mitochondrial function, and improvement of brain energy 신진대사.

2.1 항산화 효과

Studies have shown that reducing 산화 스트레스 levels in the brain may help slow the progression of AD [15]. MCT primarily 개선 neuronal reducing activity by increasing glutathione (GSH) levels and protecting neurons from oxidative damage caused by H₂O₂ and glutamate. Increased levels of transporters for glutathione, enhanced activity of neuronal γ-glutamyl synthase, and improved glutamate uptake capacity by astrocytes all contribute to 상승 GSH levels, which are then transported to mitochondria to exert antioxidant effects. Glutamate is a neurotransmitter in most excitatory neurons. After being recycled by astrocytes, it returns to neurons in the form of glutamine and is converted back into glutamate. MCT can directly inhibit glutamate receptors and alter cellular energy through mitochondrial biogenesis [16-17].

Andersen et 알다. [18]. used dynamic isotope labeling with [U-13C]C8 and [U-13C]C10 as metabolic substrates and found that caproic acid and decanoic acid undergo oxidative metabolism in mouse brain slices, with [U-13C]C10 enrichment in glutamine being particularly prominent. Following 억제 of glutamine synthesis, the accumulation of γ-aminobutyric acid (GABA) derived from [U-13C]C8 and [U-13C]C10 metabolism decreased in brain slices, confirming that the metabolism of MCT8 and MCT10 primarily occurs in astrocytes, and by increasing glutamine supply to promote GABA synthesis in neurons. Additionally, John [19], Mett [20], and others demonstrated that a 다이어트 rich in MCTs can increase acetylcholine levels in the prefrontal cortex and hippocampus, enhance catalase activity, reduce oxidative stress, and 잠재적인ly have beneficial effects on cognitive 기능 장애.

2.2 Anti-inflammatory effects

In AD patients, overactivated microglia release nitric oxide and pro-inflammatory cytokines, leading to neuropathological changes, while MCT can inhibit their 활성화 process [21]. Nishimura et 알다. [22] found that the attenuation of MCT-유도 microglia activation by lipopolysaccharide may depend on the GPR40 pathway, Lauric acid glyceride (MCT12) may reduce glial activation and neuronal damage in AD patients. Xiao et 알다. [23] validated through a rat model that targeting GPR40 can alleviate neuro염증 and improve neurological function. Additionally, compared to long-chain triglycerides, MCT produces fewer insulin-promoting signals, improves insulin sensitivity, and 줄 inflammation. Thomas et 알다. [24] evaluated the effects of replacing conventional dietary fats with MCT 기름 in humans and found no significant changes in insulin sensitivity after 6 weeks, indicating good tolerability and feasibility of MCT in humans.

2.3 Reducing brain amyloid-β (Aβ) deposition

Aβ undergoes misfolding, self-assembly, and diffusion to form Aβ deposits. Risk factors for this process include inflammation, genetic variations, and various environmental triggers [25]. Aβ peptides are derived from amyloid precursor protein (APP) through the sequential action of β- and γ-secretase, which primarily yield Aβ38, Aβ40, and the most neurotoxic Aβ42[26].

Mirzaei et 알다. [27] found that rats treated with Aβ and fed a high-fat diet exhibited memory impairments due to reduced GSH levels caused by NLRP3 inflammasome activation and oxidative stress. In contrast, rats treated with an MCT diet showed reduced gene expression 관련 with inflammasome formation and decreased oxidative stress, and MCT significantly reduced the number of Aβ-induced plaques.

Shippy et 알다. [28] used an AD mouse model and found that the metabolic product of MCT, β-hydroxybutyrate, reduced the formation of amyloid plaques, microglia proliferation, and activation of Caspase-1 by inhibiting NLRP3 inflammasome activation, demonstrating that MCT can reduce the susceptibility of primary neurons to Aβ-induced 독성, further emphasizing the neuroprotective potential of MCT.

Nafar et al. [29] administered MCT directly to mice treated with Aβ peptides and found that cortical neurons treated with Aβ peptides had significantly higher survival rates compared to neurons co-treated with coconut oil rich in MCT, and effectively alleviated Aβ-induced synaptic loss. Additionally, MCT inhibited the hypophosphorylation of Aβ-induced RAC serine/threonine kinase, glycogen synthase kinase 3, and extracellular signal-regulated kinase, further demonstrating that MCT can reduce Aβ-induced toxic effects to protect neurons.

Bansal et al. [30] found that a diet rich in MCT reduced the expression of amyloid precursor protein (APP) in N2a cells, decreased the secretion of Aβ40 and Aβ42, and promoted the differentiation of these cells, suggesting that adenosine ribosylation factor 1 (ARF1) may be involved in MCT's effects on APP expression and Aβ secretion. Additionally, knocking out ARF1 using siRNA reduced amyloid peptide secretion, demonstrating that MCT reduces ARF1 expression at both the protein and mRNA levels.

The insulin/IGF-1 (IIS) 신호 pathway is central to regulating longevity and youthfulness in mammals. Reduced IIS signaling decreases Aβ1–42 aggregation-mediated toxicity, suggesting that reduced insulin signaling may have a protective effect 반대 abnormal protein aggregation in AD [31]. Maltais et al. [32] found an association between body fat and Aβ levels in the elderly, suggesting that excessive obesity may be linked to AD pathology, further supporting the association between MCT and AD.

2.4 Protecting mitochondrial function and improving brain energy metabolism

Preventing mitochondrial dysfunction has become an important therapeutic target area. Damage to the PINK1, Nrf2, PGC1α, and PPAR-γ pathways, as well as Aβ-induced toxic effects, can impair the removal of dysfunctional mitochondria, leading to the progression of neurodegenerative 질병s [33]. Studies have shown that a diet containing MCT can maintain mitochondrial function in neuronal cells [34]. Respiratory chain synthase (CS) is exclusively present in mitochondria and serves as a marker enzyme for this organelle. After exposure to MCT for several days, CS activity significantly increased, improving brain mitochondrial function [35]. By targeting PPAR-γ receptors to supplement MCT in fibroblasts, mitochondrial function is multifaceted, potentially increasing mitochondrial biogenesis and enhancing cellular resistance to oxidative stress [36].

Studies have shown that MCT8-treated cells support fatty acid metabolism and upregulate the expression of the very long-chain acyl-CoA dehydrogenase gene (ACADVL) and CPT1, while downregulating the expression of genes involved in 포도당 metabolism (PDK3, PDK4) and upregulating genes involved in blocking glucose metabolism (PCK2) and encoding catalase (CAT). Additionally, MCT10 치료 reduced oxidative stress in cells with mitochondrial complex I defects [37], further enhancing the potential of MCTs for 완화 AD symptoms.

A prominent feature of AD in its early stages is reduced brain metabolism, primarily occurring in the parietal, temporal, and frontal cortices, which may lead to cognitive decline and AD-related pathological changes. Alternative energy sources can be used to intervene and compensate for insufficient brain metabolism [38]. MCT can provide ketone bodies as an alternative energy source for the brain and reduce the levels of Aβ40, Aβ42 levels in AD patients [15], indicating that exogenous MCT 보충 may also improve age-dependent impaired processes. Cunnane et al. [39] confirmed that MCT reduces oxidative stress damage, decreases intracellular Aβ levels, and 증가 mitochondrial complex I activity, offering potential benefits for patients with mild to moderate AD. Yomogida et al. [40] used functional magnetic resonance im노화 to observe that 20 healthy elderly participants on an MCT diet exhibited reduced brain oxygen level-dependent (BOLD) signals and decreased gray matter volume in the dorsolateral prefrontal cortex (DLPFC), indicating that MCT intake provides additional energy.

Haynes et al. [41], building on Dragano et al. [42]'s confirmation that POMC neurons express the free fatty acid receptor 1 (FFA1/GPR40), found that MCT8 rapidly transports to the mouse hypothalamus, directly activating POMC neurons via GPR40, and through non-synaptic, purine, and adenosine receptor-dependent indirect mechanisms, induce inhibitory responses, leading to changes in energy status. Additionally, MCT may activate the shuttle system by regulating astrocyte metabolism, providing fuel to adjacent neurons in the form of lactate and ketone bodies, thereby benefiting brain health [13].

3 Current status of MCT food applications for AD

Currently, MCT-based foods are being used to alleviate symptoms in AD patients. For example, the U.S. Food and Drug Administration has approved Axona © (composed of MCT) as a medical food for the treatment of AD. Sharma et al. [16] further evaluated its safety and efficacy, finding that MCTs metabolized into ketone bodies can serve as an alternative energy source for neurons in AD. Clinical trial data indicate that MCTs can improve cognitive function in patients with mild to moderate AD, with mild adverse effects (mild gastrointestinal issues).

Ota et al. [43] investigated the effects of Ketonformula © (a formula milk based on an MCT formulation) on cognitive function in AD patients. After 8 weeks of the trial, AD patients showed significant improvements in immediate and delayed logical memory tests. By week 12, AD patients demonstrated significant improvements in the digit symbol coding test and immediate logical memory test. This suggests that long-term consumption of formula containing an MCT-based formulation may have positive effects on AD patients. Studies have found that AD patients consuming coconut oil rich in MCT showed significant improvements in language memory and spatial analysis functions [44]. Additionally, consuming MCT containing caffeine may slightly increase its ketogenic effect, while emulsified MCT may enhance absorption rates and reduce the risk of adverse reactions [45].

4 결론

MCT has relatively high metabolic efficiency in the body, and different types of MCT have distinct mechanisms of action on biological organisms. MCT can enhance cognitive function in AD patients by regulating neurotransmitter effects, exhibiting antioxidant and anti-inflammatory properties, reducing Aβ deposition, protecting mitochondrial function, and improving brain energy metabolism. Further research is needed to determine the appropriate dosage of MCT-containing foods for AD patients. Current research indicates that MCT holds significant potential as a novel therapeutic option for neurodegenerative diseases such as AD, warranting further in-depth investigation and early incorporation into the daily diets of patients.

참조

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