Methionine implication on Alzheimer's disease (AD) 

 

Introduction 

Alzheimer's disease (AD) is an increasingly threatening disease to the whole population worldwide, especially at stake for the individuals aged 65 and older. AD is a neurodegenerative condition with insidious onset and progressive impairment of behavioral and cognitive functions. These functions include memory, comprehension, language, attention, reasoning, and judgment, thus affecting a person's activities of daily living. Typically, most patients with Alzheimer's disease do not have disturbances of consciousness, either early in the disease or in its midstages. The first years of the disease are hallmarked by progressive defects in learning new factual information and in recalling previously learned one. Difficulties with judgment and spatial navigation are also common. Later on, more cognitive defects and dementia aggravate the trend which develops in a letent, long term course.  

In 1906, German pathologist Alois Alzheimer described the disease and named it after him. Amyloid beta (Aβ) protein was identified as the main component of the plaques spreading on the surface of different brain zones In 1984. Aβ plaque was heralded as the unique pathological hallmark of the disease. Hardy and Higgins then proposed “the amyloid cascade hypothesis” in 1992, positing that Aβ deposits specifically in the brain are the initiating event of AD pathogenesis (Hardy and Higgins, 1992). It seemed clear that Aβ buildup sets off a cascade of damage and dysfunction in neurons, causing a series of symptoms like dementia. Toxic oligomers (Aβ40/Aβ42), the subtypes of Aβ that dissolve in some bodily fluids, had gained currency as a likely chief culprit for Alzheimer’s. Amyloid oligomers have been linked to impaired communication between neurons in vitro and in animals, and autopsies have shown higher levels of the oligomers in people with Alzheimer’s than in cognitively sound individuals. Stopping amyloid deposits became the most plausible therapeutic strategy. Hundreds of clinical trials of amyloid-targeted therapies have yielded few glimmers of promise, however. By 2006, the centenary of Alois Alzheimer’s epic discovery, a growing cadre of skeptics fretted aloud whether the field needed a reset. Many have bothered to ask, what are the genuine causes of the disease?

Other protein, Tau,  a microtubule-associated protein essential for stabilizing microtubules and facilitating axonal transport, was identified to plays a critical role in the development and progression of AD, through its involvement in neurofibrillary tangles (NFT) and neurotoxicity (Brion et al , 1991). Tau's aggregation and hyperphosphorylation disrupt neuronal function, leading to cognitive decline and neurodegeneration. Tau misfolds and forms neurofibrillary tangles that contribute to neuronal death and cognitive impairment. Besides these, the third pathological change shows a widespread synaptic loss and neuron cell death. Together with these pathological features,  amyloid protein accumulated extracellularly to form the plaque on the surface of the brain, neurofibrillary tangles disarranged fibrils in the neurons to distort the axons,  and neurons necroptosis and cell death induced atrophy of whole brain structure. The specificity of these changes are localized overlapped and/or separately, attributing to various neurological and psychological functional defects. 

Since the mechanism of the disease still remains obscure, the treatment protocols have been divergent in drudgery for long. To our best, some consensus hypotheses and studies were underlined as follows.

 

Pathological characteristics

As we mentioned before, Amyloid-β plaques and NFTs represent the defining hallmarks of AD. Amyloid-β plaques start to form in the neocortex,  subsequently affecting the diencephalon, striatum, and basal forebrain, the brainstem nuclei and the cerebellum. Synapse loss is particularly high in the immediate vicinity of amyloid-β plaques. In contrast, Tau deposits develop in the transentorhinal region, followed by fusiform and occipi totemporal gyrus, medial temporal gyrus, occipital lobe and peristriate areas, and they lastly affect the striate areas. Synapse densities are largely preserved in the immediate vicinity of intracellular NFTs. But Aβ oligomers, but not fibrils, disrupt synaptic structure and function, and induce neuroinflammatory activation preferentially targeting excitatory presynapses. Overall, amyloid-β plaques develop predominantly in neocortical and limbic brain regions with relative preservation of the cerebellum. Tau preferentially accumulates in the entorhinal cortex, hippocampus, and neocortical association cortices, largely sparing the primary sensory cortices. Therefore, Tau distribution relates more closely with the clinically most dominant dysfunction like dementia in AD, whereas amyloid-β distribution is more widespread ( Marcatti et al., 2022). Nevertheless, most of the observations were found that amyloid-β and tau oligomers are synaptotoxic and their effects are enhanced by the presence of both. These detrimental incurrences do add up.  Brains of individuals with dementia more commonly contain multiple oligomeric species in their synapses compared with healthy control brains, and the convergence of synaptic oligomers leads to a hastened cognitive decline and a faster disease progression. In fact, the interplay between oligomeric amyloid-β and tau at the synapse may be a critical step leading to synapse dysfunction (Colom-Cadena et al., 2020).

Healthy elderly display largely preserved synapse densities during normal ageing, exhibiting only minor synaptic losses of at most 15%, which are not associated with a relevant functional change. Synapse loss is typically observed in the clinically most expressive brain regions in AD, including the hippocampus, cingulate, entorhinal, and temporal cortex, whereas some brain regions are less clinically affected, such as the primary motor and sensory cortices, cerebellum, and basal ganglia, with a lesser or undetectable degree of early synapse loss.

For decades a series of reasonable causes in Alzheimer's disease have been established in anatomical structure: the extensive neuropathological changes in the entorhinal cortex and in the adjoining fields of the anterior temporal lobe cortices. As the disease progressed, the anterior temporal lobe cortices were themselves so damaged that they prevented access to unique, previously learned factual information. In effect, the bedrock of autobiographical memory was eroded. Most if not all neurons of the entorhinal cortex were turned into the diminished, the input and output lines to the hippocampus were sharply cut. The hippocampus, the brain structure needed to lock in new memories of facts elsewhere in the brain, was effectively disconnected from the entorhinal/anterior temporal lobe cortices. As a consequence, no new facts could be learned. While AD is not fatal-cause in the short term, it substantially raises vulnerability to other complications, which can eventually lead to a person's death. 

 

Risk factors 

 

AD is the biggest mysterious neuropathy associated with many unknown risk factors. The most significant factor is aging, being the primary contributor to the early on-setting. The prevalence of AD approximately doubles with every 5 years increase in age starting from age 65 years old. Age-specific incidence rates significantly increase from less than 1% yearly before 65 to 6% per year after 85. Prevalence rates increase from 10% after the age of 65 to 40% after 85. 

The apolipoprotein E (APOE) and clusterin, the strongest genetic risk factors for late-onset AD, have been identified to influence Aβ seeding and clearance. In 1991, researchers traced family-linked Alzheimer’s to mutations in the gene for a precursor protein from which amyloid derives. Research indicates that monozygotic (MZ) twins exhibit higher concordance rates for AD pathology compared to dizygotic (DZ) twins, suggesting a stronger genetic influence in MZ pairs. MZ twins show greater neuropathologic concordance, particularly for β-amyloid pathology, than DZ twins (Iacono et al., 2014).

Apolipoprotein E (APOE) is a lipid metabolism regulator with an affinity for beta-amyloid protein. There are 3 alleles for the Apolipoprotein E gene: ε2, ε3, and ε4. The ε4 allele of the APOE gene has been identified as a significant genetic risk factor for later onset of AD. Heterozygous carriers of the ε4 allele have a 3 times increased risk, while homozygous carriers face 15 times increased risk of developing AD. In patients with early onset of AD, the risk is even more pronounced in homozygous ε4 carriers and heterozygous ε4 carriers with a positive family history of AD (Karlsson et al., 2022). This duality suggests that both genetic predisposition and lifestyle choices are critical in understanding Alzheimer's disease developemnt.

AD can be inherited as an autosomal dominant disorder with nearly complete penetrance. This form of the disease is linked to mutations in 3 genes: the AAP gene on chromosome 21, Presenilin1 (PSEN1) on chromosome 14, and Presenilin 2 (PSEN2) on chromosome 1. PSEN1 and PSEN2 mutations interfere with the processing of gamma-secretase, leading to the aggregation of Aβ in the brain. Although these mutations are relatively rare, accounting for approximately 5% to 10% of all AD cases, they are strongly associated with early-onset forms of the disease. The PSEN1 mutation is the most common, accounting for about 5% of all AD cases.

Cardiovascular diseases (CVD) are recognized as significant risk factors for AD. They increase the risk of developing AD and contribute to the risk of dementia caused by strokes or vascular dementia. CVD is increasingly recognized as a modifiable risk factor for AD. Obesity and diabetes are also important modifiable risk factors for AD. Obesity can impair glucose tolerance and increase the risk of developing type II diabetes. Chronic hyperglycemia can lead to cognitive impairment by promoting the accumulation of Aβ and neuroinflammation. Obesity further amplifies the risk by triggering the release of pro-inflammatory cytokines and promoting insulin resistance.

Other potential risk factors for AD include traumatic head injury, depression, metal toxicity, higher parental age at birth, smoking, family history of dementia, increased methionine/homocysteine levels. Other factors, such as infections, and environmental pollution have been shown the correlation of the incidence of the AD, but these repressions have not been proved to be the prediction and resulting expectation of the disease.

 

AD and Methionine functions

Methionine, one of essential amino acids, is obtained from food and metabolized through the transsulfuration pathway. Methionine is converted into homocysteine by the enzyme cystathionine beta-synthase, then into another important sulfur-containing amino acid, cysteine. The methionine-homocysteine-cysteine pathway is a tightly regulated series of biochemical reactions to maintain the balance of these two sulfur-containing amino acids in the body. Folate and vitamin B12 are essential cofactors for the remethylation of homocysteine back to methionine. Folate donates a methyl group to homocysteine, which is transferred by methionine synthase, along with a methyl group from 5-methyltetrahydrofolate, to produce methionine. 

Methionine oxidation and reduction at the site of S-group is a common reaction occurring in both physiological and oxidative-stress conditions. The residue is highly susceptible to oxidation by ROS in vivo catalyzed by the methionine sulfoxide reductase (MSR) system. The levels of methionine sulfoxide (MetO) are dependent on the redox status in the cell or organ, and they are usually elevated in aging, inflammation. Quite to the opposition, the oxidation of methionine to MetO is reversible, in which a reversal to the reduction state is completed by peptide methionine (S)-S-oxide reductase (MSRA) and peptide-methionine (R)-S-oxide reductase (MSRB), which reduce the S and R conformers, respectively. Thus, these enzymes provide both an efficient repair mechanism for oxidative damage to methionine residues and general protection against oxidative stress by scavenging reactive oxygen species through the recycling of methionine (Oien et al., 2008). The regulation of the level of MetO is mediated through the ubiquitous and evolutionary conserved MSR.

The sulfoxide form has been found to comprise 10–50% of amyloid protein in amyloid plaques of AD brain (Näslund et al., 1994). A decline in MSR activity facilitates a build-up of protein-metO ( Moskovitz et al., 2016). Thus, both reduced MSR activity and the build-up of amyloid-metO increase the levels of soluble amyloid oligomers, thus forming protein aggregation. Conversely, overexpression of MSRA has been shown to protect against oxidative stress and improve survival rate (Chung et al., 2010). Increased total MSR activity, including both MSRA and MSRB, in primary rat hippocampal and cortical neurons, has been shown to prevent the sulfoxide forms of amyloid -β subform Aβ40 or Aβ42 from inducing cellular apoptosis. An elevated MSRA activity and higher MSRA mRNA levels when treated with the sulfoxide form of  Aβ42, suggested that the cells upregulated MSRA to increase cellular protection in the amyloid plaque formation ( Misiti et al., 2010).

Aβ42 has methionine present at the 35th residue in the peptide (Butterfield et al., 2011). In the AD brain, a significant fraction of Aβ42 has methionine in the form of metO. The hydrophobic surroundings around Met35 in Aβ42 are important for the oxidative, neurotoxic, and aggregation properties of Aβ42 form of metO. It has been found that lipid peroxidation initiated by oxidation of the Met35 is an early event in Aβ42 neurotoxicity (Kanski et al., 2002). Furthermore, there is a decrease in the level of MSRA, possibly increasing Met35(O)-Aβ42 formation. Moreover, in vitro studies have shown that Met35(O)-Aβ42, formed when Met35 is oxidized to the sulfoxide in Aβ 42, is toxic compared to WT-Aβ 42 and contributes to the increase of soluble A seen in the brain in AD ( Barnham et al., 2003 ). 

Rather, it is also worth mentioning that the presence of free methionine has been shown to influence Tau protein aggregation and deposition in Alzheimer's disease (AD) through various biochemical mechanisms. High levels of free methionine in the plasma can inhibit MSR activity, leading to the accumulation of oxidized proteins and promoting neurodegenerative changes (Wang et al., 2024). The inhibition of MSR by free methionine has significant implications for the development of neurodegenerative diseases. Thus far, by Methionine regulation, it has been thought that MSR plays a crucial role in reversing methionine oxidation, which is linked to oxidative stress and protein misfolding, both of which are critical factors in neurodegeneration. 

Methionine can affect tau's post-translational modifications, particularly phosphorylation, which is critical for tau's aggregation into neurofibrillary tangles (NFTs). Free methionine can modulating the phosphorylation state of tau is essential for its normal function and stability (Sonawane et al., 2021). Aberrant phosphorylation leads to Tau misfolding and aggregation, contributing to the formation of NFTs, a hallmark of AD (Šimić et al., 2016). Methionine's presence may facilitate Tau's transition from soluble forms to aggregated states through mechanisms like liquid-liquid phase separation (LLPS), which has been implicated in Tau aggregation (Wegmann et al., 2018; Lee et al., 2022).

To jump a certain conclusion, more research studies from various directions are needed. High methionine diet is associated with increased inflammation that is characteristic of neurodegenerative diseases like AD (Tapia-Rojas et al., 2015; Pi et al., 2021), limiting dietary methionine intake might be beneficial for individuals at risk of the disease.

 

Perspectives of Methionine restriction (MR)

Methionine restriction involves reducing the dietary intake of methionine while maintaining adequate intake of other essential amino acids. This intervention has been shown to induce a variety of beneficial effects, potentially impacting multiple aspects of AD pathogenesis. MR has influenced protein synthesis and turnover. It is conceivable that MR could influence the production, clearance, or aggregation of Aβ and Tau. Some studies suggest that MR can promote autophagy, a cellular process that clears misfolded and aggregated proteins, potentially reducing the burden of Aβ and NFTs. MR has been consistently shown to reduce oxidative stress in various tissues (Elshorbagy, et al., 2012). This effect is attributed to the increased production of antioxidant enzymes and decreased radical oxygen species generation. By reducing oxidative stress, MR could protect neurons from oxidative damage and cell death. MR has been shown to enhance mitochondrial biogenesis and function in various tissues (Cavuoto et al., 2015), thus protecting neurons from the detrimental effects of mitochondrial dysfunction. MR has been shown to possess anti-inflammatory properties by modulating inflammatory signaling pathways and cytokine production (Lee, & Longo, 2011). By reducing neuroinflammation, MR could potentially mitigate neuronal damage and slow the progression of AD.

However, clinical evidence on the efficacy of MR is currently limited. Some large-scale, randomized controlled trials should have specifically evaluated the effects of MR on the patients. More observational studies that individuals with low methionine diet may answer the questions why  and how MR in the prevention of developing AD, and the feasibility and safety of MR in these patients are warranted to assess the potential for future clinical trials. While the potential of dietary MR in mitigating the pathogenesis is promising, several challenges need to be addressed before it can profit off into a viable therapeutic strategy. The response to MR may vary among individuals due to genetic and environmental factors. Identifying biomarkers that predict individual responses to MR could sync up to personalize this intervention for optimal efficacy. Ultimately, a better understanding of the mechanisms underlying the effects of MR will pave the way for the development of targeted interventions that can effectively prevent or delay the progression of this devastating disease. The potential of dietary interventions, like MR, should not be overlooked in the fight against AD, given the limitations of current pharmacological approaches.

 

References：Omitted

 Key words:Methionine, Methionine restriction, Alzheimer's dissease

Writer：Dr. Haining Jin,  and Dr. Bin Xu 

蛋氨酸限制型饮食在老年性痴呆治疗中的应用分析

蛋氨酸限制型饮食（MR）通过调节代谢通路和减少神经毒性物质积累，成为阿尔茨海默病（AD）潜在的非药物干预手段。以下是其作用机制、研究证据及临床应用建议：

一、核心作用机制

1. ‌改善代谢紊乱‌：MR可降低血液中同型半胱氨酸水平，减少氧化应激对神经细胞的损伤‌2。

2. ‌调节甲基化代谢‌：蛋氨酸代谢与甲基化循环密切相关，限制其摄入可能减少异常蛋白（如β-淀粉样蛋白）的沉积‌23。

3. ‌协同锌代谢‌：蛋氨酸与锌代谢存在关联，两者联合应用可增强对AD相关症状的改善效果‌1。

二、研究证据支持

1. ‌动物实验‌：高蛋氨酸饮食诱导小鼠出现认知损伤，而改用健康饮食后，损伤可逆，提示饮食干预的时效性‌3。

2. ‌临床前研究‌：MR显著改善AD模型动物的认知功能障碍，并延长寿命，可能与改善脑内线粒体功能及减少炎症反应有关‌2。

三、临床应用建议

1. ‌适用阶段‌：

• ‌早期干预‌：适用于AD早期或高风险人群，通过调整饮食结构延缓病理进展‌36。

• ‌协同治疗‌：与胆碱酯酶抑制剂等药物联用，可能增强疗效‌8。

2. ‌饮食调整方案‌：

• ‌减少高蛋氨酸食物‌：如红肉、鱼类、鸡蛋、豆类等‌35。

• ‌增加抗氧化食物‌：补充富含维生素C、E的蔬果，以对抗氧化应激‌45。

• ‌优化脂肪酸比例‌：适量增加ω-3脂肪酸（如深海鱼）摄入，保护神经细胞膜结构‌5。

四、注意事项

1. ‌个体化差异‌：需根据患者营养状态、疾病分期调整蛋氨酸摄入量，避免营养不良风险‌6。

2. ‌长期效果待验证‌：目前研究多为短期动物实验，需更多临床研究验证MR的长期安全性及有效性‌26。

综上，蛋氨酸限制型饮食作为AD的辅助治疗手段，需结合个体化营养评估和多学科协作，以实现精准干预‌23。

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