Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study

Zhou, Qi Tony; Zheng, Hong; Chen, Jiuxia; Li, Chen; Du, Yanming; Xia, Huanhuan; Gao, Hongchang

doi:10.1007/s11011-018-0274-7

Cited by 19 publications

(16 citation statements)

References 31 publications

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“…Glucose is the major energy source of brain metabolism (Liguori et al, 2019). Impairments in brain glucose uptake and utilization have been detected in the preclinical stages of AD (Zhou et al, 2018). Furthermore, the prospective Baltimore Longitudinal Study has shown that impairments in brain glucose uptake are correlated with the reduced expression of the GLUT3 glucose transporter and subsequent development of AD (An et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice

Sun

Chen

et al. 2019

Front. Aging Neurosci.

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The accumulation of human islet amyloid polypeptide (hIAPP) in pancreatic islets under induction by a high-fat diet plays a critical role in the development of type-2 diabetes mellitus (T2DM). T2DM is a risk factor of late-onset Alzheimer’s disease (AD). Nevertheless, whether hIAPP in combination with hyperlipidemia may lead to AD-like pathological changes in the brain remains unclear. hIAPP transgenic mice were fed with a high-fat diet for 6 or 12 months to establish the T2DM model. The accumulation of amylin, the numbers of Fluoro-Jade C (FJC)-positive and β-gal positive cells, and the deposition level of Aβ42 in the hippocampi of the transgenic mice were detected by using brain sections. Cytoplasmic and membrane proteins were extracted from the hippocampi of the transgenic mice, and the ratio of membrane GLUT4 expression to cytoplasmic GLUT4 expression was measured through Western blot analysis. Changes in the cognitive functions of hIAPP transgenic mice after 12 months of feeding with a high-fat diet were evaluated. hIAPP transgenic mice fed with a high-fat diet for 6 or 12 months showed elevated blood glucose levels and insulin resistance; increased amylin accumulation, number of FJC-positive and β-gal positive cells, and Aβ42 deposition in the hippocampi; and reduced membrane GLUT4 expression levels. hIAPP transgenic mice fed with a high-fat diet for 12 months showed reductions in social cognitive ability and passive learning ability. A high-fat diet increased amylin accumulation in the hippocampi of hIAPP transgenic mice, which presented AD-like pathology and behavior characterized by neural degeneration, brain aging, Aβ42 deposition, and impaired glucose utilization and cognition.

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Section: Discussionmentioning

confidence: 99%

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice

Sun

Chen

et al. 2019

Front. Aging Neurosci.

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“…As a downstream product of α-KG, succinyl-CoA may be reduced due to the downregulation of the pathway enzymes influencing the TCA cycle. However, there may be upregulation of succinate and aspartate (Zhou et al, 2018). Other enzymes and metabolites related to the metabolic process (e.g., citric acid, cis-aconitic acid, and fumaric acid) are decreased (Zheng et al, 2018).…”

Section: Altered Tca Cycle and Oxphos In Aging And Admentioning

confidence: 99%

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

Wang

et al. 2020

Front. Neurosci.

119

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Alzheimer's disease (AD) is an incurable neurodegenerative disease. Numerous studies have demonstrated a critical role for dysregulated glucose metabolism in its pathogenesis. In this review, we summarize metabolic alterations in aging brain and ADrelated metabolic deficits associated with glucose metabolism dysregulation, glycolysis dysfunction, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) deficits, and pentose phosphate pathway impairment. Additionally, we discuss recent treatment strategies targeting metabolic defects in AD, including their limitations, in an effort to encourage the development of novel therapeutic strategies.

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“…Although AD and T2D have been demonstrated to correlate with each other, more data are still needed to elucidate the underlying molecular mechanisms. Metabolomics can reveal metabolic profile changes of living systems in response to external stimuli [27][28][29] and has proven to be valuable in the investigation of molecular mechanisms underlying various human diseases, including Alzheimer's disease [30][31][32][33][34][35][36]. In this study, the combined use of nontargeted metabolomics, metabolic correlation analysis, and multiple statistical approaches was applied to detect the metabolic alterations of the serum and pancreatic tissues of APP/PS1 mice at different time points during AD progression.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Alzheimer’s disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice

et al. 2019

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Increasing evidence suggests that there is a correlation between type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD). Increased Aβ polypeptide production in AD patients would promote metabolic abnormalities, insulin signaling dysfunction and perturbations in glucose utilization, thus leading to the onset of T2D. However, the metabolic mechanisms underlying the interplay between AD and its diabetes-promoting effects are not fully elucidated. Particularly, systematic metabolomics analysis has not been performed for the pancreas tissues of AD subjects, which play key roles in the glucose metabolism of living systems. In the current study, we characterized the dynamic metabolic profile alterations of the serum and the pancreas of APP/PS1 double-transgenic mice (an AD mouse model) using the untargeted metabolomics approaches. Serum and pancreatic tissues of APP/PS1 transgenic mice and wild-type mice were extracted and subjected to NMR analysis to evaluate the functional state of pancreas in the progress of AD. Multivariate analysis of principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were conducted to define the global and the local (pancreas) metabolic features associated with the possible initiation of T2D in the progress of AD. Our results showed the onset of AD-induced global glucose metabolism disorders in AD mice. Hyperglycemia and its accompanying metabolic disorders including energy metabolism down-regulation and oxidative stress were observed in the serum of AD mice. Meanwhile, global disturbance of branched-chain amino acid (BCAA) metabolism was detected, and the change of BCAA (leucine) was positively correlated to the alteration of glucose. Moreover, increased level of glucose and enhanced energy metabolism were observed in the pancreas of AD mice. The results suggest that the diabetes-promoting effects accompanying the progress of AD are achieved by down-regulating the global utilization of glucose and interfering with the metabolic function of pancreas. Since T2D is a risk factor for the pathogenesis of AD, our findings suggest that targeting the glucose metabolism dysfunctions might serve as a supplementary therapeutic strategy for Alzheimer's disease.

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Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study

Cited by 19 publications

References 31 publications

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

Interplay between Alzheimer’s disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice

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