Mechanism of high-fat diet causing metabolic cognitive decline in lipid metabolism disorders

doi:10.21203/rs.3.rs-4346360/v1

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Mechanism of high-fat diet causing metabolic cognitive decline in lipid metabolism disorders

https://doi.org/10.21203/rs.3.rs-4346360/v1

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Recent findings support the notion that High fat homeostasis can cause dementia progressively. We investigate the relationship between glucose intolerance and cognitive impairment. Increasing body weights with high fat diet in transgenic mice in which the low-density-lipoprotein receptor (LDLr) was deleted, induce the glucose intolerance. This metabolic disorder for long period make the integrity of blood-brain barrier on hippocampal region disrupt and cognitive impairment. Cognitive dysfunction includes decreased short-term and working memory and motor functioning.

Fasting blood glucose due to high fat intake in transgenic mice in which the low-density-lipoprotein receptor (LDLr) was deleted, and traced the association between metabolic disorders and the blood-brain barrier, and the alignment and integrity of the hippocampal region. And we tried to confirm the changes in motor ability and cognitive function through behavioral analysis.

Therefore, this study investigated the effects of high-fat diet exposure on cognitive function, motor performance, blood-brain barrier (BBB) integrity, and hippocampal array changes in transgenic mice with ablated LDLR receptor (LDLr). We also wanted to determine changes the adverse effects of these changes on the development of dementia caused by a high-fat diet. It was confirmed that stabilization and permeability of the BBB structure deteriorated due to a high-fat diet, and genes expressed in precursors for neurogenesis were reduced. The BBB regulates the transport of molecules into the central nervous system (CNS) maintaining tight control over the chemical composition of the nervous environment required for proper nerve function. In this sense, it can be hypothesized that high-fat diet-induced BBB dysfunction alters the neurogenic environment contributing to cognitive impairment. Changes in the BBB structure resulted in weakening of the cortical and hippocampal arrangements, and prolonged high-fat diets resulted in general motor and cognitive dysfunction.

Dementia

High fat diet

low-density-lipoprotein receptor

metabolic dementia

Obesity

Metabolic-cognitive syndrome

Dementia appears when the brain is damaged by injury or disease, and has a negative impact on progressive impairment of memory, thinking, and behavior and activities in daily life. Except for memory disorders, the most common symptoms include negative emotions, speech disorders, and decreased motivation.^1,2 These dementia are classified as neurocognitive disorder (NCD) with various subclasses, and many NCDs can be caused by other medical conditions or disorders. As one of them, the occurrence of neurocognitive disorders due to metabolic disorders has recently emerged. Metabolic-cognitive syndrome (MetS) refers to negative effects on cognitive ability and brain structure due to metabolic disorders .^3,4

Metabolic syndrome is a syndrome with hypertension, hyperglycemia, or hyperuricemia.⁵ Genetic, environmental, and lifestyle factors contribute to metabolic syndrome and are involved in the development of both neurological and metabolic diseases. Recently, increased synthesis and secretion of low-density lipoprotein (LDL) has been shown to increase triglyceride synthesis, which is expected to increase the risk of Alzheimer's disease and vascular dementia. LDL is a group of lipoproteins that transport all lipid molecules throughout the body outside the cell. Lipids transported include all fat molecules such as cholesterol, phospholipids, and triglycerides.⁶ When cells need additional cholesterol, they synthesize LDLrand PCSK9 that breaks down LDLr. ⁷ LDLr is inserted into the protoplasmic membrane, and LDL in the bloodstream is endocytosis into the cell and transferred to the endosome. Oxidized LDLs are LDL particles with modified structural components. Lipids and proteins of LDL can be oxidized in the walls of blood vessels by free radical, and oxidized LDL is a potential risk factor for cardiovascular disease. LDLr is a mosaic protein that mediates endocytosis of cholesterol-rich LDL. It is a cell surface receptor that recognizes very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), ApoB100 embedded in LDL particles, and ApoE. LDLr maintains the plasma level of LDL.^8–12

High-fat diet (HFD) can have serious adverse effects not only on metabolic diseases such as obesity, diabetes, and arteriosclerosis, but also on the brain. In an animal model in which LDLR was knocked out, it was confirmed that a high-fat diet caused greater metabolic disorders and cognitive disorders. ^13,14

However, high levels of LDL are associated with an increased risk of cardiovascular disease and are involved in atherosclerosis, which is oxidized within the arterial wall. Atherosclerosis is an arteriosclerosis disease pattern in which abnormalities occur due to lesions in the arterial wall. ^15–17 These lesions can be narrowed by accumulation of atherosclerotic plaque.¹⁸ Flakes are made up of fat, cholesterol, calcium, and other substances found in the blood. Arterial stenosis restricts the flow of oxygen-rich blood to body parts. There are generally no symptoms in the early stages of the outbreak, but symptoms begin to appear with age. In severe cases, coronary artery disease, stroke, etc. can occur depending on the affected arteries.^19,20

The exact cause is unknown and is suggested as pluralistic. Risk factors include abnormal cholesterol levels, elevated inflammatory markers, high blood pressure, diabetes, and obesity.

The carotid artery supplies blood to the brain and neck. Significant stenosis of these carotid arteries can indicate dizziness, mild cognitive impairment, blurred vision and facial paralysis, headaches, and significant stenosis or closure of arteries to the brain can cause stroke in severe cases.

Atherosclerosis is associated with inflammatory processes in endothelial cells of the vascular wall. ^21,22 Therefore, we hypothesized that LDL clearance metabolic disorder due to lack of LDL receptor can contribute to decreased brain blood flow and decreased brain cognitive function due to neuroinflammation.

Recently, various hypotheses and studies are being conducted on the association between diet and nutrients and dementia risk in various studies. In fact, obesity and diabetes are recognized as risk factors for Alzheimer's disease in various epidemiological studies. Furthermore results of various clinical cases and meta-analyses also showed that the risk of dementia was high in the high BMI population.

The increase in the incidence of cardiovascular disease due to a high-fat diet was devised as a factor, such as cholesterol and fat, that narrows the arteries, changes the body's metabolism, and increases protein levels, potentially causing cognitive impairment and reduced motor function.

Animal

Five-week-old C57BL/6J mice (Jackson Laboratories) and Ldlr^-/- mice on the C57BL/6J (Jackson Laboratories) background were used. All mice were approved by Institutional Animal Care and Use Committee of the SoonChunHyang University (IACUC No. SCH SCH21-0005) and were bred at SounChunHyang Institute of Medi-Bio Science Animal Center. The mice were housed at 12 hours light-dark cycle with temperature 23℃ ± 1 ~ 2, humidity 50%±5. 50%±5. The number of animals in each group was 7 and statistical processing was performed.

The mice were monitored each cages for body weight, temperature, and paralysis twice a week until stabilization after surgery. After the end of all experiments, euthanasia proceeds with Co₂ gas after the same inhalation anesthesia.

Animal grouping

To determine the difference between metabolic changes and disorders in early and late metabolic syndrome, the normal radiant diet was PicoLab Rodent Diet 20 (5053, Fat 5%) and the high-fat diet Research Diets (D12492, Fat 60%) after 1 week of adaptation. Randomly selected and cages are separated according to the experimental groups. Purchased from and provided. Mice were fasted for 8 hours prior to blood glucose check with a glucose meter and blood glucose measurement strip (Roche Diabetes, Inc, USA), then the distal part of the tail was cut off, a drop of blood was released, and the strip was dotted to measure. For glucose-tolerance tests(GTT), overnight-fasted mice were injected intraperitoneally with glucose (1g/kg). GTT was performed in 10-12weeks old male and female control and LDLR-/- mice. Blood glucose levels were measured at the basal level and at 15, 30, 60 and 120 min after glucose or insulin administration using One Touch Ultra2 Blood Glucose Meter (Accu-Check Guide).

Metabolic system monitoring

In order to confirm the metabolic change, a metabolic cage (Tse Systems, Germany) experiment was conducted that could comprehensively check energy consumption, respiratory exchange rate, food and water consumption, and exercise activity. The first 48 h were considered an acclimatization period and only the data collected during the 3 day and 4 day was used in the calculations.

Dual energy X-ray

Lean body mass check was performed with a Dual energy X-ray absorptiometry (InAlyzer, MediKors, South Korea). Before start scanning mice were anesthetized with 2% isoflurane in O₂.

Behavior tests

All behavioral analyzes were performed at Experimental Animal Center of Soonchunhyang Institute of Medi-Bio Science (SIMS, Cheonan, South Korea) and were conducted in a custom chamber (Domestic, South Korea) to reduce experimental deviation, and white noise was performed together. While white noise was present at approximately 60 dB. Additionally, all experiments except the Passive avoidance test were analyzed and used using Smart v3.0 software (Panlab, Barcelona, Spain). Passive avoidance tests were analyzed using the Shut avoidance program for the experiment (Panlab, Barcelona, Spain). A significant difference was confirmed through the unpaired t-test by conducting the experiment three times. ²³

Open field test and light and dark

The open field test (Domestic, South Korea) and light and dark test is a test that can check motor activity and anxiety. Used 45 x 45 x40 diameter square open field. Experiment time was 10 min for each subjects Each mouse was placed in the middle of the field. Center zone and Periphery zone were all light intensity was 390 lux. And light and dark test while the small chamber is closed and dark. Each mouse was placed in the dark box. After 5s, the door was opened.

Y-maze test

The Y-maze (Domestic, South Korea) is a test that can short-term memory and index of locomotor activity. Experiment time was 8 mins for each subject. Each mouse was placed in the arm A at the beginning. Zones were A, B, C, center in maze box. To checked correct alteration/number of total entries. Light intensity was 390 lux.

Barnes maze

The Barnes-maze test (Domestic, South Korea) is a test that can evaluate learning and memory, and cognitive flexibility. Apparatus was circular black platform, 90 in diameter with 18 holes. Experiment stage: box 1) training phase is 3 min to find and enter the escape. box 2) probe phase: remove the escape box and the time spent in the quadrant where the escape box was originally located. Each mouse was placed in the middle of the apparatus. Zones were time spent in the quadrant (Target zone), target hole, error zone. Repeated this experiment for 4 days. Light intensity was 390 lux.

Rotarod test

The Rotarod test (Panlab, Barcelona, Spain) is a test that can evaluate the motor coordination and balance.

Strat speed is 4 rpm and Acceleration rate is20rpm/min. At 10 sec after placing the mouse on the rod, start acceleration, and note the speed at which the mouse falls off. Repeat the experiment 3 times and calculate the average of the endurance time and RPM to derive the result.

Passive avoidance

The passive avoidance test (Harvard apparatus, USA) is a test of long-term memory based on fear. Placed a mouse in the light compartment. Put the mouse in the main box and give it a search time for 1 minute. After 1 min, the door was opened, the mouse could enter the dark compartment. After the mouse entered the dark compartment 2 sec, the door was closed. And the mouse was given an electric shock for 5 sec. Repeated this experiment for 4 days. Light intensity was 390 lux at main box.

Reverse-Transcription Quantitative Real-Time PCR

After being harvested, the frozen left hemisphere of each mouse (200 mg) was prepared and homogenized. To determine the mRNA expression levels of the target genes, total RNA was extracted from the mouse brain tissue using an easy-BLUE™ Total RNA Extraction Kit (iNtRON, Daejeon, Korea) according to the manufacturer’s protocol. The concentration and quality of the isolated RNA were determined using a NanoDrop spectrophotometer (NanoDrop Technologies, LLC; Wilmington, DE, USA). Next, cDNA was synthesized using 2 µg total RNA with an All-in-One 5 × First Strand cDNA Master Mix (CellScript, Madison, WI, USA), and quantitative real-time PCR (qRT-PCR) was performed using TOPreal™ qPCR 2X PreMIX (Enzynomics, Daejeon, Korea) according to the manufacturer’s protocol. Ang2, Tie2, Zo-1, Zo-2, Oilg2, Nes, Dlg4, and Cux1 mRNA transcript levels were detected using the CFX Connect Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA).

Statistical analysis

All behaivor test values are expressed as the mean ± SEM. All statistical analyses were performed using GraphPad Prism 8 software (GraphPad, La Jolla, CA, USA). For the Real-Time PCR, data were analyzed using standard deviation (SD) followed by significant differences were analyzed using one-way ANOVA followed by Tukey's multiple comparison test.

Lack of LDLr and a high-fat diet affect blood sugar levels and weight in the body over time.

To select when the deficiency of LDLr affects body metabolism, each group divided by diet and gene was measured for body weight and fasting blood glucose. (Fig. 1).

Data from the start week (week 0) were not included in the graph because all objects were within the deviation range. From the 2nd week after adjusting the diet of each WT and LDLr-/- group, the group receiving HFD increased slightly compared to the group receiving body weight NCD. The WT NCD group and the LDLr-/- NCD group, which had different genotypes but no dietary differences, showed low body weight, while the WT HFD group and LDLr-/- HFD group showed high body weight over time.

All groups also measured blood sugar levels after an empty stomach for 12 hours. Hungry blood sugar did not show much difference in the second week of diet control, but it showed differences over time. From the 8th week of diet control, the LDLr-/- HFD group recorded an overwhelmingly high fasting blood sugar level compared to other groups. On the other hand, the same genotypes, LDLr-/- NCD groups, WT NCD and WT HFD groups, were higher than in the early stages, but did not show any differences between groups.

After 8 weeks, body weight and fasting blood glucose no longer show a large gap, which is why we divided them into early (diet-controlled 2 weeks) and late (diet-controlled 8 weeks) in subsequent experiments (Fig. 2).

Decreased general exercise and cognitive decline due to LDLr deficiency and high-fat diet may be associated with energy metabolism.

Metabolic cage was performed to visually identify small changes in the mouse to metabolic changes along with changes in body weight and fasting blood glucose. Metabolic cage measures and records the gas exchange ratio of O2 consumed and CO2 emitted by mice in their lives, indirect measurement of energy consumption, activity, and consumption of food and drinking water (Fig. 3).

Metabolic cage test was conducted for 10 days to confirm the metabolic system changes caused by the HFD diet. According to dietary changes, it was confirmed that drink consumption in each group fell at HFD (Fig. 3A). Daily food intake was also seen to drop in both the HFD group (Fig. 3B). The 24h respiratory exchange rate (RER) could confirm a significant difference between groups, but the difference between diet groups was not significant (Fig. 3C). Although it was possible to confirm the amount of activity that was not proportional to the diet (Fig. 3D), energy expenditure (EE) did not show the same pattern. In the Late LDLR-/- HFD group, activity was low while energy consumption was high, indicating that the metabolic system was inefficient (Fig. 3E).

As a result group that suffered a lack of LDL receptors and prolonged high-fat diets showed less food intake and drinking water supply, and less active but consuming the same or more energy, indicating a decrease in metabolic efficiency.

The effects of metabolic disorders and prolonged intake of high-fat diets on vascular maturation and vascular-brain barriers were confirmed.

Ang2 induces vascular maturation, and Tie2 acts as an antagonist to inactivate it. Although the group experienced healthy wild types and metabolic disorders, there was no significant difference in Ang2 and Tie2 expression in the group who consumed HFD along with metabolic disorders confirmed reduced expression of Tie2 with a high increase in Ang2 expression (Fig. 4A).

In addition, Zo-1/2, a Blood-brain barrier marker, is a tightly bound protein that regulates the structural stabilization and permeability of BBB, and compared to healthy wild types that consume NCD, the metabolic disorder group that suffers metabolic disorders and decreases the mRNA expression level of Zo-1/2 as the period of HFD.(Fig. 4B).

Effects of Metabolic Disruption and Prolonged Intake of High-Fat Diet on BBB Structure and Neurotransmission. Olig2 encodes the endothelial-peripheral-oligodendrosite that constitutes the BBB structure, and Nestin is a marker expressed in precursors for nerve production. There was no difference in the wild-type and NCD-eating groups, but metabolic disorders and HFD-eating groups reduced markers that make up the BBB structure and reduced levels of neuro-precursor markers (Fig. 5A).

In addition, Dlg4, an NMDA receptor marker that accommodates neurotransmitters, showed high mRNA levels in healthy wild types, but decreased marker expression levels in groups suffering from metabolic disorders and in groups consuming HFD (Fig. 5B). Recent studies have linked variants in the expression of Dlg4 to autism spectrum disorder (ASD) and other Williams' syndrome. Overweight and obesity are prevalent in at least 50% of individuals with ASD, and further studies using variants in this gene are warranted.

Thus, LDLr deficiency and prolonged high-fat diet exacerbate cortical and hippocampal cell arrangement and integrity.

The cerebrum, which occupies the largest part of the brain, is covered by the cerebral cortex. The cerebral cortex is the center that determines higher-order functions such as sensory, motor, and language. In the cerebral cortex, neurons are well-placed and sparsely packed with surprising density. Degenerative brain diseases such as Alzheimer's and Parkinson's can lead to the death of nerve cells in the brain, accelerating the symptoms. As a result of confirming changes in the cerebral cortex caused by the high-fat diet, changes in cell density due to dietary changes could not be confirmed in the WT group (Fig. 6A and B). However, in the LDLR-/- group, as the high-fat diet was prolonged, the cell density in the cerebral cortex decreased and the expression of apoptosis cells increased (Fig. 6C to E).

It is known that only nerve cells in a specific area proliferate in the brain, and the hippocampus is a representative area among them. It plays a central role in essential networks of memory in the brain. In particular, CA2 of the cornu ammonis (CA) of the hippocampus is an area that remembers and relies on social behavior to generate memory traces, and when a high-fat diet was performed for a long time, apoptosis cell expression could be confirmed in the CA2 band. In this way, when the behavior analysis is performed, there is a problem with the search function, which may be related to the delay time (Fig. 6A to E).

LDLr deficiency and prolonged high-fat diet lead to a decrease in general exercise. To confirm the effect of changes in body metabolism and mRNA level due to LDLr deficiency and prolonged high-fat diet on general motor activity, open field tests and light and dark tests were conducted. To measure the distance traveled in the Openfield laboratory, all mice were free to move and the total distance (cm) was measured through camera tracking software. Subsequently, the area was divided in half to form a dark room with no light in half, and the mouse was able to move freely with the light zone, starting with the dark zone. We measured the number of times between dark and light zones and the time spent under the light zone.

In the Open field test (Fig. 7A), there was no difference between the WT and early LDLr-/- NCD groups, but the early LDLr-/- HFD groups had small differences. In addition, in the late LDLr-/- group, both the NCD and HFD groups significantly decreased activity compared to WT, and the degree was more severe in the HFD group.

In Light and dark (Fig. 7B), there was no difference in transition between the WT and early LDLr-/- groups, but there was a significant difference in both the NCD and HFD groups in the late LDLr-/- groups, showing a more severe decrease in transition in the HFD group. The time spent in the light zone was not significant in all groups.

In addition, a rotarod test was conducted to confirm the effect of LDLr deficiency and high-fat diet on basic physical strength such as endurance (Fig. 7C). In the rotarod test, the WT mouse recorded a long delay time regardless of the equation. However, the early LDLr-/- NCD group recorded a slight decrease in latency compared to the WT, and the early LDLr-/- HFD group recorded a very low latency with the late LDLr-/- group.

LDLr deficiency and prolonged high-fat diet lead to decreased cognitive function.

Each group was tested for cognitive function to determine whether LDLr deficiency and prolonged high-fat diet affected the degradation of brain function, such as memory and cognitive function.

Y maze can check the mouse's spatial work memory scale. The mouse freely shifts each arm in the shape of a Y out of curiosity to explore a zone that has never been visited before. In the ymaze test, there was no difference between the WT and early LDLr-/- groups depending on the gene and dietary type. However, the late LDLr-/- group showed low working memory in both NCD and HFD (Fig. 8A).

Passive avoidance and Barnes-maze were performed to check long-term memory. Passive avoidance results of memorizing negative effects can confirm the results that the LDLR-/- HFD groups have the most difficulty remembering. It was confirmed that WT HFD did not negatively affect memory (Fig. 8B).

In the Barnes-maze test, which tests the positive effect of learning and remembering the location of food and searching for food, the Late LDLr-/- HFD group, who had been on the high-fat diet for the longest time, had the highest time to search for food and reach it despite repeated training. It took a long time (Fig. 8C,D).

Therefore, it can be confirmed that the high-fat diet habit of LDLr-/- mice also damages memory along with changes in the hippocampal area.

Among the various factors that cause dementia, various studies have suggested the possibility of a link with LDLR metabolic syndrome.^24,25

LDLRr mediates the endocytosis of cholesterol-rich low-density lipoproteins that regulate plasma cholesterol levels. It is highly expressed in the liver and is also expressed in the stomach, heart and brain. Knock out of the Ldlr gene increases circulating cholesterol by more than 2 times and LDLR by more than 7 times. It also causes a significant increase in blood lipid concentration, and high-fat diet intake causes atherosclerosis at an early stage and is associated with obesity, metabolic disorders, and cognition. Disability and overall decline in exercise capacity can be expected.^26–28

As expected, it was confirmed that the fasting blood glucose level increased with the increase in body weight in the LDLR-/- HFD group, compared to the LDLR-/- group, which ate the normal diet. Although fat was included in the general diet, it did not cause obesity, and it was confirmed that the long-term exposure to high-fat feed increased weight change and blood glucose. Based on these results, further research is needed on the maintenance and formation of adipose tissue according to the weight change caused by the high-fat diet.²⁹

Recent studies have shown that high blood cholesterol can increase the risk of certain types of dementia, such as Alzheimer's disease and vascular dementia.³⁰ In fact, our study confirmed that the expression of Ang2, a gene that induces vascular maturation, increases with diet period due to long-term high-fat diet intake, and confirmed a decreasing pattern of ZO-1/2, a gene of vascular-brain barrier. The blood-brain-barrier (BBB) is a very complex and dynamic barrier. It consists of capillary brain endothelial cells that provide protective functions and a network of pericytes that maintain these functions. Under normal conditions, the BBB is highly regulated, but metabolic stress can lead to dysfunction of the neurovascular unit and disrupt BBB structure. Thus, with the prolonged high-fat diet, Olig2, a marker that constitutes the BBB structure, decreased, confirming changes in the BBB structure. These results are consistent with our findings in histopathology.

Also, interestingly, this study confirmed the downregulation of Dlg4. This gene is a risk gene that causes diseases and genes linked to autism due to the transmission of incorrect nerve signals through synapses, and recent research results have confirmed its connection to obesity-related diseases. Therefore, we would like to suggest a new direction for the mechanism causing Dementia due to metabolic disorder through additional research on the relevant gene.

An open field test and a light and dark test were conducted to confirm the general motor activity, but it was confirmed that the activity decreased in the late LDLR-/- HFD. In the light and dark test, it was confirmed that the late LDLR-/- HFD group transition was most reduced. In addition, a rotarod test was conducted to confirm changes in basic physical strength such as endurance, and the late LDLR-/- HFD group recorded a very low latency.

It was confirmed through H&Estaining that obesity induced by a high-fat diet in LDLR-/- mice deteriorated the cell arrangement and integrity of the hippocampus, and the impairment of hippocampal electromechanical memory was confirmed through Y-maze, Passive avodiance and Barnes-maze.

However, it was confirmed that C57BL/6 mice exposed to the high-fat diet did not show cognitive or motor function deterioration, which can be expected due to changes caused by the high-fat diet in the LDLR-/- environment.

Long-term high-fat diets in the LDLR-/- group also induced changes in the metabolic system. It was confirmed that the respiratory exchange ratio (RER) decreased due to a significant decrease in the amount of food and drinking water. Although the amount of activity in the metabolic cage decreased, energy expenditure (EE) was high. It can be confirmed that the long-term high-fat diet caused disproportionate metabolic disorders.

In conclusion, it was confirmed that even differences in high-fat diets could lead to cognitive impairment and motor memory problems due to imbalance in the metabolic system. In addition, the instability of the BBB structure ultimately caused by the high-fat diet and the change in the hippocampal structure can lead to cognitive impairment and loss of motor ability, and the possibility that high-fat metabolism disorder caused by the usual eating habits can lead to dementia suggests.

Our study needs to further investigate the mechanisms involved in the link between high-fat diet-induced cognitive impairment and motor dysfunction. Long-term high-fat diet changes the density and structure of the cerebral cortex and hippocampus, which can explain cognitive impairment and motor function deterioration, but sufficient research on the exact mechanism is needed. Recently in several diseases, changes in BBB structure and brain damage are linked, suggesting the possibility of neuroinflammation, and neuroinflammation is known to mechanisms. Therefore, it is necessary to elucidate the in-depth molecular mechanisms for the possible involvement of high-fat diet-induced neuroinflammation. Finally as the high-fat diet lasts for a long time, it is necessary to confirm the correlation between changes in cell density in the cortex and the findings of apoptosis cells.

This section is not mandatory but may be added if there are patents resulting from the work reported in this manuscript.

Author Contributions: Conceptualization,O.JS.; methodology,E.C.L.; software,D.H.L.; validation, O.JS.; formal analysis, E.C.L.; investigation,D.H.L.; resources, O.JS.and S.D.C.;data curation, J.S.O.; writing—original draft preparation, J.S.O.; writing—review and editing, E.C.L.;J.SO.; visualization, E.C.L;J.S.O.; supervision J.S.O.; project administration, J.S.O.; funding acquisition, J.S.O. All authors have read and agreed to the published version of the manuscript.

Funding: This research was supported by a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HC22C0043) by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (2023RA1A2C100531). The authors wish to acknowledge the financial support of The Catholic University of Korea Uijeongbu St. Mary’s Hospital Clinical Research Laboratory Foundation made in the program year of 2023.

Institutional Review Board Statement: Not applicable

Informed Consent Statement: Not applicable

Data availability statements: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Acknowledgments: We would like to thank Soonchunhyang Biomedical Research Core Facility of Korea Basic Science Institute (KBSI), Uijeongbu St. Mary's Hospital of Korea, Republic and The Catholic University of Korea

Conflicts of Interest: The authors declare no conflict of interest.

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Mechanism of high-fat diet causing metabolic cognitive decline in lipid metabolism disorders

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