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Midlife Chronological and Endocrinological Transitions in Brain Metabolism: System Biology Basis for Increased Alzheimer’s Risk in Female Brain

Wang, Yiwei, Shang, Yuan, Mishra, Aarti, Bacon, Eliza, Yin, Fei, Brinton, Roberta·2020·Scientific Reports
DOI 10.1038/s41598-020-65402-5PMC PMC7244485
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Abstract

Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer’s disease (LOAD). Comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. Chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. Coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LOAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer’s disease.

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Figures

Figure 1 Principle component analysis of hippocampal gene expression. PC1 can be explained by both chronological aging and endocrinological aging. Chronological aging has a stronger impact on the trancriptomic profile, especially post-menopausal, which led to a unique aging brain state.
Figure 1 Principle component analysis of hippocampal gene expression. PC1 can be explained by both chronological aging and endocrinological aging. Chronological aging has a stronger impact on the trancriptomic profile, especially post-menopausal, which led to a unique aging brain state.CC BY · PubMed Central
Figure 2 Gene expression of hippocampal electron transport chain subunits and bioenergetics regulators during endocrinological and chronological aging. Panel (a), nuclear encoded OXPHOS genes; (b), mitochondrial encoded OXPHOS genes; (c), expression of mitochondrial transcriptional factors, RNA polymerase POLRMT and DNA polymerase POLG; (d), gene expression of key bioenergetics regulators. *p < 0.05 in comparison to the previous column.
Figure 2 Gene expression of hippocampal electron transport chain subunits and bioenergetics regulators during endocrinological and chronological aging. Panel (a), nuclear encoded OXPHOS genes; (b), mitochondrial encoded OXPHOS genes; (c), expression of mitochondrial transcriptional factors, RNA polymerase POLRMT and DNA polymerase POLG; (d), gene expression of key bioenergetics regulators. *p < 0.05 in comparison to the previous column.CC BY · PubMed Central
Figure 3 Glycolysis and TCA cycle intermediates and key enzyme gene expression. Panel (a), glycolysis intermediates and lactate level; (b), TCA cycle intermediates and derivatives level; (c), gene expression of key enzymes involved in glycolysis; (d), gene expression of key enzymes involved in TCA cycle. *p < 0.05 in comparison to the previous column. #p < 0.05 in comparison to Reg 6 mo.
Figure 3 Glycolysis and TCA cycle intermediates and key enzyme gene expression. Panel (a), glycolysis intermediates and lactate level; (b), TCA cycle intermediates and derivatives level; (c), gene expression of key enzymes involved in glycolysis; (d), gene expression of key enzymes involved in TCA cycle. *p < 0.05 in comparison to the previous column. #p < 0.05 in comparison to Reg 6 mo.CC BY · PubMed Central
Figure 4 Brain amino acids levels (a) and gamma-glutamyl amino acids levels (b). *p < 0.05 compared to Reg 9 mo group.
Figure 4 Brain amino acids levels (a) and gamma-glutamyl amino acids levels (b). *p < 0.05 compared to Reg 9 mo group.CC BY · PubMed Central
Figure 5 Brain ketone body level (a) and expression of genes involved in ketone body metabolism (b). *p < 0.05 in comparison to the previous column. #p < 0.05 in comparison to Reg 6 mo.
Figure 5 Brain ketone body level (a) and expression of genes involved in ketone body metabolism (b). *p < 0.05 in comparison to the previous column. #p < 0.05 in comparison to Reg 6 mo.CC BY · PubMed Central
Figure 6 Glycolipids metabolism and expression of relevant genes. Panel (a), brain triglyceride levels; (b), DHAP, glycerol, and glycerol 3-phosphate levels; (c), gene expression of lipogenesis and lipolysis enzymes; (d), brain monoacylglycerol levels; (e), brain diacylglycerol levels. Lipids arranged by increased unsaturation and total carbon number from top to bottom for panels (a,d,e). *p < 0.05 compared to the previous column.
Figure 6 Glycolipids metabolism and expression of relevant genes. Panel (a), brain triglyceride levels; (b), DHAP, glycerol, and glycerol 3-phosphate levels; (c), gene expression of lipogenesis and lipolysis enzymes; (d), brain monoacylglycerol levels; (e), brain diacylglycerol levels. Lipids arranged by increased unsaturation and total carbon number from top to bottom for panels (a,d,e). *p < 0.05 compared to the previous column.CC BY · PubMed Central
Figure 7 Fatty acid metabolism. Panel (a), level of free fatty acid (FFA) levels in the brain; (b), level of acyl-carnitine levels in the brain; (c), gene expression of genes involved in fatty acid metabolism and β-oxidation. *p < 0.05 compared to the previous column. #p < 0.05 to Reg 6 mo group. &p < 0.05 to Reg 9 mo group.
Figure 7 Fatty acid metabolism. Panel (a), level of free fatty acid (FFA) levels in the brain; (b), level of acyl-carnitine levels in the brain; (c), gene expression of genes involved in fatty acid metabolism and β-oxidation. *p < 0.05 compared to the previous column. #p < 0.05 to Reg 6 mo group. &p < 0.05 to Reg 9 mo group.CC BY · PubMed Central
Figure 8 Plasma lipidomic analysis. Panel (a), free fatty acid levels; (b), acylcarnitine and free carnitine levels; (c), triglyceride (TAG) levels. *p < 0.05 to the previous column. #p < 0.05 to Reg 6 mo.
Figure 8 Plasma lipidomic analysis. Panel (a), free fatty acid levels; (b), acylcarnitine and free carnitine levels; (c), triglyceride (TAG) levels. *p < 0.05 to the previous column. #p < 0.05 to Reg 6 mo.CC BY · PubMed Central
Figure 9 Correlation of brain and plasma lipid profiles at each chronological and endocrinological aging stage. Panel (a), Reg 6 mo; (b), Reg 9 mo; (c), Irreg 9 mo; (d), Acyc 9 mo; (e), Acyc 15 mo; (f), summary of significant correlations between brain and plasma lipid species. Dark red indicates negative correlation, and bright yellow indicates positive correlation. FFA, free fatty acid; MAG, monoacylglycerol; DAG, diacylglycerol; TAG, triacylglycerol; SM, sphingomyelin; CER, ceramide; HCER, hexosylceramid; DCER, dihydroceramide; PC, phosphatidylcholine; PE, phosphatidylethanolamine; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; CE, cholesterol ester.
Figure 9 Correlation of brain and plasma lipid profiles at each chronological and endocrinological aging stage. Panel (a), Reg 6 mo; (b), Reg 9 mo; (c), Irreg 9 mo; (d), Acyc 9 mo; (e), Acyc 15 mo; (f), summary of significant correlations between brain and plasma lipid species. Dark red indicates negative correlation, and bright yellow indicates positive correlation. FFA, free fatty acid; MAG, monoacylglycerol; DAG, diacylglycerol; TAG, triacylglycerol; SM, sphingomyelin; CER, ceramide; HCER, hexosylceramid; DCER, dihydroceramide; PC, phosphatidylcholine; PE, phosphatidylethanolamine; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; CE, cholesterol ester.CC BY · PubMed Central
Figure 10 Dynamic metabolic aging in female brain during chronological and endocrinological aging. Decline in glucose metabolism results in utilization of amino acids as an interim metabolic fuel alternative, followed by activation of fatty acid metablism, as oxidative phosphorylation continues to decline.
Figure 10 Dynamic metabolic aging in female brain during chronological and endocrinological aging. Decline in glucose metabolism results in utilization of amino acids as an interim metabolic fuel alternative, followed by activation of fatty acid metablism, as oxidative phosphorylation continues to decline.CC BY · PubMed Central

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Metadata

Authors
Wang, Y., Shang, Y., Mishra, A., Bacon, E., Yin, F., & Brinton, R.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-05-22
Volume
10
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-020-65402-5
PMC
PMC7244485
Cited by
42
References
9
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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