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Redox Biol—Xinong Liu Zhigang et al. revealed for the first time that methionine-restricted diets can improve AD cognitive dysfunction

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Written by - Liu Zhigang, Zhang Yuyu edited - Wang Sizhen, Fang Yiyi edited - Wang Sizhen
Alzheimer's disease Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia, and is becoming a global threat to human health [1].

Neuropathological alterations of A D manifest as accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles caused by aggregated amyloid β (Aβ) and hyperphosphorylated tau, respectively, leading to cognitive impairment and dementia [2]
。 Dietary interventions are a potential nutritional strategy to prevent cognitive decline [3].

Methionine restriction (MR) has been found to improve the metabolic state of the disorder and prolong life [4, 5].

In addition, recent studies by the team of researchers have demonstrated the neuroprotective and antioxidant effects of MR in rodent models [6, 7].

This may be because MR activates cystathionine-β β-synthase (CBS) in the transsulfidation pathway ) and cystathionine-γ γ-lyase (CGL) to produce hydrogen sulfide (H _2S) [8], partially involved in cellular redox balance regulation
.
However, MR improves neurodegenerative diseases such as AD and CBS/_H2S The mechanism of participation in the pathway has not yet been clarified
.

Recently, Professor Liu Zhigang of the College of Food Science and Engineering of Northwest A&F University and others in Redox, a high-level journal in the field of international redox biology Biology first published the title "Methionine restriction-Association with redox homeostasis and implications on aging and diseases.
" In a review article, the authors systematically elaborate on the link between methionine restriction and redox status in aging and related diseases.

The review article was co-authored
by Dr Annika Höhn of the German Institute of Human Nutrition.

Professor Liu Zhigang and others published a title entitled " Effects of methionine intake on cognitive function in mild cognitive impairment patients and APP/PS1 Alzheimer's Disease model mice: Role of the cystathionine-β-synthase/H₂S pathway" research paper, the authors first studied in a survey of 45 people diagnosed with mild cognitive impairment (Mild Cognitive Impairment, MCI) and a cohort of 61 healthy controls without cognitive impairment found a positive association
between methionine intake and an increased risk of MCI.
After MR intervention on female and male APP/PS1 AD model mice, it was found that MR sex specifically improved cognitive dysfunction, mitochondrial dysfunction and oxidative stress in male APP/PS1 AD model mice.
This can be partly explained by the fact that MR activates the CBS/_H2S pathway
in the brain.
This series of studies reveals for the first time that methionine-restricted diets are a potential nutritional dietary pattern
for improving AD-related cognitive dysfunction.
Dr.
Min Hou of Shanghai Jiao Tong University and Dr.
Shi Lin of Shaanxi Normal University participated in the cooperation, and the research was also supported by Professor Liu Xuebo of Northwest A&F University , guidance support
from Professor Til man Grune, German Institute for Human Nutrition.

Regression analysis shows the relationship between methionine intake quartiles and MCI risk (Figure 1A)
。 The MCI case group had higher dietary methionine intake, dietary methionine as a percentage of total energy, and dietary methionine as a percentage of total protein compared to the non-case-control group (Figure 1B-C).

These results (Figure 1) show that dietary methionine intake is positively correlated
with MCI risk.

Figure 1The MCI group had less dietary methionine intake than the control group

(Source: Xi, et al.
, RedoxBiology, 2022).

To evaluate the effect of MR on cognitive function in AD mice, the authors performed the Morris water maze experiment
.
MR increases the escape latency of male wild-type mice in the 5-day navigation test with no effect on females (Figure 2G).

On the probe test day (day 6), MR increases the time
spent in the target quadrant by male AD mice rather than female mice.
Conversely, MR reduces the time spent in the target quadrant for male and female wild-type mice (Figure 2H).

These results (Figure 2) suggest that MR can specifically improve cognitive function
in male AD mice rather than females.

Figure 2 MR improves cognitive function in male APP/PS1 AD mode mice (Source: Xi, et al.
, Redox Biology, 2022)
MR treatment significantly reduced Aβ accumulation in male and female cortex and hippocampal CA1 region (Figure 3A-B).

mRNA expression
of the Aβ precursor APP and the lyase BACE1 were also detected.
MR treatment significantly inhibits APP mRNA expression in male and female cortex (Figure 3C).

In addition, MR significantly reduced BACE1 mRNA levels in the cortex of male AD mice, but not in female AD mice (Figure 3D）
。
Figure 3 MR reduced Aβ deposition in the brains of male and male APP/PS1 AD mode mice (Source: Xi, et al.
, Redox Biology, 2022)
The ultrastructure of hippocampal synapses is mainly involved in cognition and memory
.
Excessive accumulation of Aβ can lead to synaptic ultrastructural damage[9].

The results showed that MR increased the length and width of postsynaptic density (PSD) in male AD mice, but not in female AD mice (Figure 4A-B）
。 And mRNA levels of PSD-95, a key synaptic protein, were also increased in the brains of MR-treated male AD mice, but not in female AD mice (Figure 4C).

Thus, these results (Figures 3-4) indicate that MR reduces Aβ accumulation in the brains of male and female AD mice, and MR restored synaptic ultrastructure
in male AD mice instead of female mice.

Figure 4 MR improved the synaptic ultrastructure of the brains of male APP/PS1 AD mode mice (Source: Xi, et al.
, Redox Biology, 2022)
Normal mitochondrial function plays a key role in maintaining synaptic plasticity [10].

MR can reverse damaged mitochondrial morphology in male AD mice, but not female AD mice (Figure 5A).

The number of neuronal mitochondria in male AD mice is significantly reduced and the rate of damage is significantly increased (Figure 5B).

MR significantly increased the number of hippocampal mitochondria in male AD mice and mitigated mitochondrial damage, but this was not the case in female AD mice (Figure 5B
。
A decrease in the mtDNA/nDNA ratio indicates a decrease in mitochondrial biogenesis [11].

After 4 months of MR, the mtDNA/nDNA ratio in the cortex of male AD mice was significantly increased (Figure 5C)
。 MR increased COX5b mRNA levels (a gene associated with mitochondrial function) in the cortex of male AD mice, but not in female AD mice (Figure 5D).

。 These data (Figure 5) suggest that MR improves brain mitochondrial function and enhances mitochondrial biogenesis
in male AD mice rather than female mice.

Figure 5 MR improved mitochondrial morphology and biosynthesis in the brains of male APP/PS1 AD mode mice (Source: Xi, et al.
, Redox Biology, 2022)
Mitochondria are one of the main producers of ROS [12]
。 MR significantly reduced the GSSG/GSH ratio in male AD mice, but not in female mice (Figure 6A).

。 MR significantly reduced GSH levels in the cortex of male wild-type mice and increased GSSG levels (Figure 6B-C).

。 In addition, MR significantly reduced MDA (a biomarker of oxidative damage) in the cortex of male AD mice, but not in female AD mice (Figure 6D).

Endogenous _H2S is thought to be a redox active molecule produced by the key catalytic enzyme CBS[13]
。 MR significantly increased serum and cortical H2Slevels in male AD mice, but not in females (Figure 6E)
。 MR increased mRNA and protein expression of CBS in the brains of male AD mice, but not in female AD mice (Figure 6F-J).

These results (Figure 6) suggest that MR may reduce oxidative stress and activate CBS/H in a sex-specific manner in the brains of male AD mice rather than female mice ₂S pathway
.

Figure 6 MR maintained redox homeostasis in the brains of male APP/PS1 AD mode mice and activated CBS/_H2S pathway (Source: Xi, et al.
, RedoxBiology, 2022).

Article conclusion and discussion, inspiration and prospects

In summary, the study found in studies on populations that lower dietary methionine intake was associated with
improved cognitive function.
While no sex differences were observed between dietary methionine intake and MCI risk in population studies, MR can specifically reduce cognitive decline and oxidative stress in AD mice, which can be partially explained by the activated CBS/_H2S pathway
。 The authors' findings suggest that MR may be an effective nutritional intervention for cognitive decline and is consistent
across species.
The relationship between dietary methionine intake and cognitive function in AD patients should be further studied, and preclinical trials
of MR in AD patients can be appropriately conducted in the absence of protein malnutrition.
Since low protein intake in older adults may cause muscle mass loss and heart failure [14-15], it may be more appropriate
to maintain or even increase protein intake in older adults, as well as to keep methionine intake low.
This can be achieved by using plant protein sources, which are typically lower in methionine compared to animal protein and therefore may have beneficial effects [16].

Review article: https://doi.
org/10.
1016/j.
redox.
2022.
102595 research article: https://doi.
org/10.
1016/j.
redox.
2022.
102595

Corresponding author: Liu Zhigang (left), first author: Xi Yujia (middle), Zhang Yuyu (right).

(Photo courtesy of Liu Zhigang's group)

About the author (swipe up and down to read).

Corresponding author: Liu Zhigang, Ph.
D.
, professor, doctoral supervisor
.
He was selected as a national young talent, the German "Humboldt Scholar", the United States "Cornell University Down · Cornell-Chinese Scholar", "Shaanxi Provincial Association for Science and Technology Young Talents Recruitment Program", was a visiting professor
in the Department of Food Science, Cornell University.
He is currently the deputy director of the Department of Food Nutrition at the College of Food Science and Engineering of Northwest A&F University, a visiting researcher at the German Institute of Human Nutrition, a section editor of Food and Humanity Nutrition and Health, and an associate editor
of the journal Frontiers in Aging Neuroscience.
His main research interests include the interaction mechanism between dietary pattern and entero-brain health, the exploration of food nutritional functional components and efficacy evaluation, etc
.
He has presided over more than ten projects such as the Science and Technology Innovation 2030 Brain Science and Brain-like Research Major Project, the National Natural Science Foundation of China Project, and other projects, in Cell Metabolism, Nature Communications, Brain Behavior and Immunity He has published more than 80 papers
in the Journal of Agricultural and Food Chemistry.
Contact: zhigangliu@nwsuaf.
edu.
cn personal web https://food.
nwsuaf.
edu.
cn/szll/js/spyyx/89298a307d52432aaa73869a62f86496.
htm
First author: Xi Yujia, master, born in 1996, graduated from the College of Food Science and Engineering, Northwest A&F University.

First author: Yuyu Zhang, master, born in 1998, master's degree in College of Food Science and Engineering, Northwest A&F University
。

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