Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma

Johnson, Lance A.; Zuloaga, Kristen L.; Kugelman, Tara; Mäder, Kevin; Morré, Jeff; Zuloaga, Damian G.; Weber, Sydney; Marzulla, Tessa; Mulford, Amelia; Button, Dana; Lindner, Jonathan R.; Alkayed, Nabil J.; Stevens, Jeffrey S.; Raber, Jacob

doi:10.1016/j.ebiom.2015.12.008

Cited by 62 publications

(55 citation statements)

References 106 publications

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“…We also found IL-12p70 and IL-13 to be closely related to high insulin levels in APP/PS1xdb/db mice, both of which have been shown to be elevated in prediabetic patients [62]. A similar trend has been observed for IL-12p70 in HFD-fed mice [91]. Altogether, multivariate analysis of cytokine expression in the cortex from our mixed model indicates that there are marked proinflammatory differences in cytokine profiles associated with the co-presentation of T2D and AD pathologies.…”

Section: Discussionsupporting

confidence: 79%

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Sankar

Infante-Garcia

Weinstock

et al. 2020

J Neuroinflammation

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Background: Diabetes is a risk factor for developing Alzheimer's disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aβ pathology and increased expression of glial activation markers in APPswe/ PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. Methods: To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. Results: Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1β, and MCP-1) and proinflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aβ1-40, Aβ1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. Conclusions: Altogether, our multiplexed analysis of cytokines shows that Alzheimer's and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aβ and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD.

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Section: Discussionsupporting

confidence: 79%

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Sankar

Infante-Garcia

Weinstock

et al. 2020

J Neuroinflammation

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“…Interestingly, the cognitive impairments we observed in HFD fed E3 and E4 mice were not observed in a model of Type 1 Diabetes (T1D) – as we have previously observed in wildtype mice22 – suggesting that these negative cognitive effects are specific to the background of HFD-induced obesity and IR. However, many studies have demonstrated cognitive dysfunction in rodent models of T1D,23 and discrepancies with our results could be due to a number of factors including mouse age, sex and strain, the specific cognitive tasks employed, and delivery method of STZ (intracerebroventricular vs intraperitoneal vs intravenous).…”

Section: Discussionsupporting

confidence: 70%

Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

Johnson

Torres

Impey

et al. 2017

Sci Rep

Self Cite

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Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia.

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“…108 Finally, animal studies support the findings in man and also demonstrate that resolving obesity improves cognitive performance. 109–111 Switching mice from a HFD to a regular diet to reduce caloric intake results in improved metabolic health, with increased insulin sensitivity and improvement in cognitive function. These improvements are associated with reduced blood brain barrier-leakage, decreased glial activation, and increased vascular perfusion.…”

Section: Neurological Benefits Of Targeting Obesitymentioning

confidence: 99%

“…These improvements are associated with reduced blood brain barrier-leakage, decreased glial activation, and increased vascular perfusion. 109–111 …”

Section: Neurological Benefits Of Targeting Obesitymentioning

confidence: 99%

Neurological consequences of obesity

O’Brien

Hinder

Callaghan

et al. 2017

The Lancet Neurology

369

261

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Obesity, primarily a consequence of poor dietary choices and an increased sedentary lifestyle, has become a global pandemic that brings with it enormous medical, social, and economic challenges. Not only does obesity increase the risk of cardiovascular disease and certain cancers, but it is also recognized as a key driver of other metabolic syndrome (MetS) components. These components include insulin resistance, hyperglycemia with prediabetes or type 2 diabetes, dyslipidemia, and hypertension, and are underlying contributors to systemic metabolic dysfunction. More recently, obesity and diet-induced metabolic dysfunction have been identified as risk factors for the development of a wide variety of neurological disorders in both the central and peripheral nervous systems. An abundance of literature has shown that obesity is associated with mild cognitive impairment and altered hippocampal structure and function, and there is a robust correlation between obesity and Alzheimer’s type dementia. Similarly, many reports show that both the autonomic and somatic components of the peripheral nervous system are impacted by obesity. The autonomic nervous system, under control of the hypothalamus, displays altered catabolic and anabolic processes in obese individuals attributed to sympathetic-parasympathetic imbalances. A close association also exists between obesity and polyneuropathy, a complication most commonly found in prediabetic and diabetic patients, and is likely secondary to a combination of obesity-induced dyslipidemia with hyperglycemia. This review will outline the pathophysiological development of obesity and dyslipidemia, discuss the adverse impact of these conditions on the nervous system, and provide evidence for lipotoxicity and metabolic inflammation as the drivers underlying the neurological consequences of obesity. In addition, this review will examine the benefits of lifestyle and surgical interventions in obesity-induced neurological disorders.

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Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma

Cited by 62 publications

References 106 publications

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

Neurological consequences of obesity

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