Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction

Stoeckel, Luke E.; Arvanitakis, Zoe; Gandy, Samuel E.; Small, Dana M.; Kahn, C. Ronald; Pascual‐Leone, Álvaro; Pawlyk, Aaron C.; Sherwin, Robert S.; Smith, Philip J.

doi:10.12688/f1000research.8300.2

Cited by 82 publications

(71 citation statements)

References 152 publications

(180 reference statements)

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“…Even small advances may offer the opportunity to have an important influence on decreasing the large and growing burden of two of the most important public health challenges of the 21st century. Collaborative efforts, across different scientific disciplines and across all stakeholders including the public and governmental agencies, are underway to move toward improving the lives of those with, or at risk for, T2D and dementia .…”

Section: Discussionmentioning

confidence: 99%

Review: Relationship of type 2 diabetes to human brain pathology

Pruzin

Nelson

Abner

et al. 2018

Neuropathology Appl Neurobio

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Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high-mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially nonvascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms. The clinicopathological studies to date demonstrate T2D to be consistently associated with infarcts, particularly subcortical lacunar infarcts, but not ADNC, suggesting the association of T2D with dementia may largely be mediated through CVD. Furthermore, growing interest exists in insulin resistance (IR), particularly IR within the brain itself, which may be an associated but distinct phenomenon from T2D, and possibly itself associated with ADNC. Other mechanisms largely related to protein processing and efflux in the central nervous system with altered function in T2D may also be involved. Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta-amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels. Medical research is ongoing to further disentangle the relationship of T2D to dementia in the ageing human brain.

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Section: Discussionmentioning

confidence: 99%

Review: Relationship of type 2 diabetes to human brain pathology

Pruzin

Nelson

Abner

et al. 2018

Neuropathology Appl Neurobio

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“…It has been suggested that metabolic syndrome (MetS) and its components are important risk factors of mild cognitive impairment, age-related cognitive decline, vascular dementia, and Alzheimer’s disease [4, 5]. Although some potential mechanisms have been proposed, there is still a big knowledge gap at identifying roles and molecular mechanisms that underlie obesity and other individual components of the MetS in developing predementia and dementia syndromes [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

“…However, it would also be very important to develop a newly proposed disease-course modification strategy toward early and effective risk factor management that could be clinically significant in reducing the risk of metabolic and cognitive decline [7]. Since individual risk factors or MetS components may independently impair metabolic and cognitive function, one ideal intervention approach is to simultaneously control multiple obesity-related metabolic dysfunction and pro-inflammatory pathways [7, 13].…”

Section: Introductionmentioning

confidence: 99%

“…Since individual risk factors or MetS components may independently impair metabolic and cognitive function, one ideal intervention approach is to simultaneously control multiple obesity-related metabolic dysfunction and pro-inflammatory pathways [7, 13]. In this study, we aimed to test one of the disease-course control strategies that target multiple metabolic dysfunctions for early prevention and/or mitigation of the neurocognitive complications associated with obesity and diabetes.…”

Section: Introductionmentioning

confidence: 99%

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FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice

et al. 2017

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Accumulating studies suggest that overnutrition-associated obesity may lead to development of type 2 diabetes mellitus and metabolic syndromes (MetS). MetS and its components are important risk factors of mild cognitive impairment, age-related cognitive decline, vascular dementia, and Alzheimer’s disease. It has been recently proposed that development of a disease-course modification strategy toward early and effective risk factor management would be clinically significant in reducing the risk of metabolic disorder-initiated cognitive decline. In the present study, we propose that fibroblast growth factor 21 (FGF21) is a novel candidate for the disease-course modification approach. Using a high-fat diet (HFD) consumption-induced obese mouse model, we tested our hypothesis that recombinant human FGF21 (rFGF21) administration is effective for improving obesity-induced cognitive dysfunction and anxiety-like behavior, by its multiple metabolic modulation and anti-pro-inflammation actions. Our experimental findings support our hypothesis that rFGF21 is protective to HFD-induced cognitive impairment, at least in part by metabolic regulation in glucose tolerance impairment, insulin resistance, and hyperlipidemia; potent systemic pro-inflammation inhibition; and improvement of hippocampal dysfunction, particularly by inhibiting proneuroinflammation and neurogenesis deficit. This study suggests that FGF21 might be a novel molecular target of the disease-course-modifying strategy for early intervention of MstS-associated cognitive decline.

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“…The exact mechanism of brain insulin signaling is clinically relevant, since it has been reported that neuronal insulin signaling is impaired in dementia (Stoeckel et al . ); the reduction in IR expression by presenilin, and the repression of an active IR conformation by major histocompatibility complex class I, as mentioned in the previous section, were suggested to contribute to the causative role of presenilins and of brain inflammation in Alzheimer's disease (AD) (Maesako et al . ; Dixon‐Salazar et al .…”

Section: Ir In Alzheimer's Diseasementioning

confidence: 99%

The neuronal insulin receptor in its environment

Gralle

2016

Journal of Neurochemistry

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Insulin is known mainly for its effects in peripheral tissues, such as the liver, skeletal muscles and adipose tissue, where the activation of the insulin receptor (IR) has both short-term and long-term effects. Insulin and the IR are also present in the brain, and since there is evidence that neuronal insulin signaling regulates synaptic plasticity and that it is impaired in disease, this pathway might be the key to protection or reversal of symptoms, especially in Alzheimer's disease. However, there are controversies about the importance of the neuronal IR, partly because biophysical data on its activation and signaling are much less complete than for the peripheral IR. This review briefly summarizes the neuronal IR signaling in health and disease, and then focuses on known differences between the neuronal and peripheral IR with regard to alternative splicing and glycosylation, and lack of data with respect to phosphorylation and membrane subdo-main localization. Particularities in the neuronal IR itself and its environment may have consequences for downstream signal-ing and impact synaptic plasticity. Furthermore, establishing the relative importance of insulin signaling through IR or through hybrids with its homolog, the insulin-like growth factor 1 receptor, is crucial for evaluating the consequences of brain IR activation. An improved biophysical understanding of the neuronal IR may help predict the consequences of insulin-targeted interventions. Abbreviations used: AD, Alzheimer's disease; AbO, b-amyloid oligomer; AMPAR, a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor; ERK, extracellular signal-regulated kinase; GABA A R, c-aminobutyric acid receptor, class A; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IR, insulin receptor; IR-A, isoform A of the insulin receptor; IRS, insulin receptor substrate; NMDAR, N-methyl-D-aspartate receptor; PI3K, phosphatidylinositol-4,5-bisphosphate-3-kinase; Shc, Src homology 2 domain containing.

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Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction

Cited by 82 publications

References 152 publications

Review: Relationship of type 2 diabetes to human brain pathology

Review: Relationship of type 2 diabetes to human brain pathology

FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice

The neuronal insulin receptor in its environment

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