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Written by Xu Jingjing, edited by Yuan Linhong - Wang Sizhen, Fang Yiyi Editor—Summer Alzheimer's disease (AD) is the most common type of dementia, accounting for about 60%-70%.
AD is expected to affect approximately 135 million people in 2051 as the population ages[1].
However, there is currently no effective treatment for AD, so effective prevention strategies are urgently needed to reduce the public health burden
of AD.
Previous studies have shown that diets rich in long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) have a dose-dependent protective effect on cognitive function in older adults [2],, However, many clinical randomized controlled trials have not reached consistent research conclusions [3].
Apolipoprotein E (ApoE) is an important molecule
involved in lipid metabolism in peripheral tissues and the central nervous system.
There are 3 alleles commonly found in the ApoE gene (ε2, ε3 and ε4 Three different protein isomers (ApoE2, ApoE3, and ApoE4) [4], ApoE ε4 has been shown to be an independent genetic risk factor for AD [5,6].
Studies have shown that there is an ApoE-isoform-dependent effect
in the process of uptake and transport of PUFAs in brain tissue.
In ApoE ε4 carriers, the integrity of the blood-brain barrier (BBB) is impaired, the transport capacity of lipids decreases [7,8], and ApoE4 promotes extracellular activities in the brain Aβ aggregation[9].
Current evidence suggests that dietary supplementation with docosahexaenoic acid (DHA) can attenuate the role of ApoEε4 in combination with β-amyloid (Aβ) by anti-inflammatory and antioxidant mechanisms The role associated with AD pathological processes [10].
However, the neurospecific effects and exact mechanisms of DHA therapy associated with ApoE status remain to be studied
.
Recently, Yuan Linhong's research group of Capital Medical University published a report entitled " Discrepant Modulating Effects of Dietary Docosahexaenoic Acid on Cerebral Lipids, Fatty Acid Transporter Expression and Soluble Beta-Amyloid Levels inApoE -/-and C57BL/6J mice" explores defects in the ApoE gene and the effects of DHA dietary interventions on the brain Effects of
Aβ production and lipid levels.
Jingjing Xu and Xiaochen Huang are the co-first authors of this paper, and Professor Yuan Linhong is the corresponding author
.
In this study, the investigators found that DHA intervention was effective for ApoE root knockout (ApoE-/- ) and wild-type C57BL/6J (C57 wt) mice had different effects on brain lipid, fatty acid transporter expression, and soluble Aβ levels, indicating DHA The effect on animal brain lipid levels and Aβ metabolism is related
to the body's ApoE status.
In the study, the researchers administered a 5-month control diet or DHA intervention
to ApoE-/- and C57 wt mice.
As shown in Figure 1A, ApoE-/- mice had elevated
cerebral cortical TC levels compared to C57 wt mice.
Compared to the control diet-fed animals, both DHA-intervened C57wt and ApoE-/- mice had significantly lower cerebral cortical TC levels, and The decline was even greater
in C57 wt mice.
Compared to C57 wt mice, ApoE-/- mice showed lower cerebral cortical HDL-C and higher LDL-C levels
。 DHA intervention significantly increased the cerebral cortical HDL-C level of C57 wt mice, but did not affect the ApoE-/- mouse cerebral cortex HDL-C level
.
DHA-assisted C57wt mice had significantly increased cerebral cortical LDL-C levels, but ApoE in DHA intervention -/- A downward trend
is shown in mice.
The brain-cortical HDL-C/LDL-C ratio of ApoE-/- mice was significantly lower than that of C57 wt mice
.
After DHA intervention, this ratio increased significantly in both C57 wt and ApoE-/- mice
.
ApoE-/- Cerebral cortical TG and apolipoprotein B (ApoB) in mice and C57wt mice There was no significant difference in the level; DHA intervention increased C57wt mouse cerebral cortical TG levels (P < 0.
05), but not in ApoE -/- TG levels in the cerebral cortex in mice showed a downward trend
.
DHA intervention had no significant effect on C57wt and ApoE-/- cerebral cortical ApoB levels in mice, although in ApoE -/- There is a slight increase trend
in mice.
As shown in Figure 1B, C57wt and ApoE-/- mouse cerebral cortex HMGCR There was no significant difference in the expression of ACAT1 protein, and its expression level was not affected by
DHA intervention.
Cortical lipid levels and expression
of molecular proteins related to lipid metabolism in C57 wt and ApoE-/- mice.
(Source: Jingjing Xu, et al.
, NAN, 2022)
This study also found that ApoE-/- The expression of ABCA1 protein in the cerebral cortex and hippocampus of mice was significantly higher than that of C57 wt mice
.
After DHA intervention, ABCA1 protein expression was upregulated in C57 wt mice, but downregulated in ApoE-/- mice (Figure 1C).
Compared to C57 wt mice, ApoE-/- mice had lower levels of cortical and hippocampal LXRα/β proteins.
After DHA intervention, the expression of LXRα/β in the cerebral cortex and hippocampus of C57 wt mice was reduced, especially in C57 wt male mice.
However, after DHA intervention, the expression of LXRα/β in the cerebral cortex and hippocampus of ApoE-/- mice increased (Figure 1D).
）
。
Together, these data show that ApoE-/- mice exhibit spontaneous cerebral lipid metabolism abnormalities
.
Dietary DHA intervention can affect brain lipid levels in C57wt and ApoE-/- mice by regulating the expression of molecules related to brain lipid metabolism.
Figure 2.
C57 wt and ApoE-/- expression
of mouse cortical fatty acids and molecular genes and proteins associated with fatty acid transport.
(Source: Jingjing Xu, et al.
, NAN, 2022)
Compared with C57 wt mice, ApoE-/- The ratio of n-6 PUFAs to n-6/n-3 PUFAs in the cerebral cortex of mice was higher, but only the difference in n-6/n-3 fatty acid ratio was statistically significant
.
The DHA intervention diet significantly increased the levels of DHA and n-3 PUFAs in the cerebral cortex of ApoE-/mice
。 In ApoE-/- mice, the ratio of n-6/n-3 fatty acids in the cerebral cortex after DHA intervention decreased
significantly.
In the C57 wt and ApoE-/- mouse cerebral cortex given DHA intervention feed, n-6 PUFAs The content remained unchanged (Figure 2A).
The expression of Fabp5mRNA in the cerebral cortex of ApoE-/- mice was significantly lower than that of C57 wt Mouse
.
DHA intervention reduced C57wt and ApoE-/- mouse cerebral cortical Fabp5 mRNA expression and lowest
expression in ApoE-/- mice.
The expression of Cd36mRNA in the cerebral cortex of mice was also lower
than that of C57 wt mice.
DHA intervention reduced the expression of Cd36mRNA in the cerebral cortex of C57wt mice, but not in ApoE -/- mice increased its expression
.
The expression of ApoE-/- mouse cerebral cortical Scarb1mRNA was higher than that of C57 wt mice
.
DHA intervention significantly induced Scarb1mRNA expression
in ApoE-/- mice.
DHA-intervened C57wt and ApoE-/- FABP5 in the mouse cerebral cortex The expression of proteins showed an increasing trend; Compared with C57 wt mice, the expression of SRB1 protein in the cerebral cortex of ApoE-/- mice was slightly higher, but there was no significant difference between groups (Figure 2B).
In conclusion, although no protein expression differences in fatty acid transporters were found in the study, gene expression levels of fatty acid transport-related molecules in the cerebral cortex were influenced
by ApoE status and dietary DHA interventions.
In addition, DHA intervention caused changes in cerebral cortical fatty acid levels, especially in the cerebral cortex of ApoE-/- mice with DHA intervention, where DHA levels increased significantly
。
Figure 3.
C57 wt and ApoE-/- cortical soluble Aβ (sAβ) content of mice Molecular gene and protein expression
associated with Aβ metabolism.
(Source: Jingjing Xu, et al.
, NAN, 2022)
ApoE-/- soluble Aβ in mouse brain 1-42 The levels were significantly higher than in C57 wt mice
.
DHA intervention for C57wt and ApoE-/- soluble Aβ 1-40 in the cerebral cortex of mice The level of ApoE-/- soluble Aβ1-42 in the mouse cerebral cortex had no effect; But increased the level of soluble Aβ 1-42 in the cerebral cortex of C57wt mice and resulted in Aβ 1-40/Aβ1-42 in the cerebral cortex The ratio drops
.
The expression of BACE1 protein in the cerebral cortex of ApoE-/- mice was significantly lower than that of C57 wt mice, DHA The intervention had no effect on the expression of BACE1 protein in the cerebral cortex (Figure 3A).
The expression of ApoE-/- mRNA in the cerebral cortex of mice was significantly higher than that of C57 wt Mouse
.
DHA intervention further induced C57wt and ApoE-/- App in mouse cerebral cortex Expression
of mRNA.
After DHA intervention, cortical IdemRNA expression was upregulated
only in ApoE-/- mice.
The expression of cerebral cortical IDE protein in ApoE-/- mice is lower than that in C57 wt mice, and DHA The expression of cerebral cortical IDE protein after intervention showed a downward trend
in mice with both genotypes.
DHA intervention significantly downregulated the expression of Lrp1mRNA in the ApoE-/- mouse cortex, but to both mouse cerebral cortex The expression of LRP1 protein had no effect
.
The expression of Sorl1mRNA in the cerebral cortex was lower in ApoE-/- mice than in C57 wt mice
。 DHA intervention for C57wt and ApoE-/- mouse cerebral cortical Sorl1 The expression of mRNA had no effect； The expression of cortical SorLA protein in C57 wt mice showed a downward trend, but the difference was not statistically significant (Figure 3B).
。
The authors found that the status of ApoE may affect the amount of soluble Aβ in the mouse cerebral cortex; Moreover, the changes in soluble Aβ content of the cerebral cortex caused by DHA are ApoE status dependent
.
The authors also observed significant differences in gene and protein expression of Aβ metabolism-related molecules in C57wt and ApoE-/- mice, and that these molecules were paired Response to DHA interventions was also inconsistent
.
The authors speculate that the net effect of gene and protein expression of molecules associated with Aβ metabolism induced by DHA intervention may ultimately determine soluble Aβ levels
in mouse brains.
Conclusion and discussion, inspiration and prospects
In summary, ApoE deletion may trigger a series of compensatory changes in signaling molecules involved in brain cholesterol balance, fatty acid uptake, and Aβ production.
The results of this study suggest that ApoE plays an important role in DHA interventions to alter brain fatty acids, cholesterol, and Aβ production.
DHA interventions can significantly affect the expression of brain lipid and cholesterol reverse transport molecules and regulate the production of Aβ in the brain, a process that may be affected
by deletion of the ApoE gene.
Of course, further research is needed to reveal the specific mechanisms by
which DHA and ApoE genotypes affect lipid and Aβ metabolism in the brain.
Original link: https://doi.
org/10.
1111/nan.
12855
Xu Jingjing and Huang Xiaochen are the co-first authors of the paper, Professor Linhong Yuan is the corresponding author
of the paper.
This study was jointly supported by the National Natural Science Foundation of China (82173508 and 81973027) and the Special Project for the Construction of High-level Health Technology Talents in Beijing Health System (No.
2022-3-032).
Corresponding author profile:
Yuan Linhong, professor and doctoral supervisor of Capital Medical University, and member of the Basic Nutrition Branch of the Chinese Nutrition Society; Member of Special Nutrition Branch of Chinese Nutrition Society; Director of
Beijing Nutrition Society.
Mainly engaged in the research of
nutritional intervention and nutritional prevention of chronic diseases.
As the first person in charge, he undertook 5 projects of the National Natural Science Foundation of China; 1 project of Beijing Natural Science Foundation; More than 10 projects from
other sources.
He has published more than 60 scientific research papers, including more than 30 papers included in SCI by the first and corresponding authors
in international journals.
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