The effects of insulin and insulin-like growth factor I on amyloid precursor protein phosphorylation in in vitro and in vivo models of Alzheimer's disease

Kim, Bhumsoo; Elzinga, Sarah; Henn, Rosemary E.; McGinley, Lisa M.; Feldman, Eva L.

doi:10.1016/j.nbd.2019.104541

Cited by 49 publications

(41 citation statements)

References 111 publications

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“…One of the most important known risk factors for developing AD is diabetes [ 24 ]. Several studies have demonstrated impaired insulin signaling and insulin resistance in the brain to AD pathogenesis [ 25 – 28 ]. A growing body of evidence suggests ketones can significantly improve glucose homeostasis which in turn reduces insulin resistance and metabolic dysfunction [ 29 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

Shippy

Wilhelm

Viharkumar

et al. 2020

J Neuroinflammation

158

110

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Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

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Section: Resultsmentioning

confidence: 99%

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

Shippy

Wilhelm

Viharkumar

et al. 2020

J Neuroinflammation

158

110

View full text Add to dashboard Cite

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“…Circulating IGF-I is produced mainly from the liver but it can be produced by any cell type. The receptors of IGF-I are on almost all different cells including brain and have neuroprotective effects[ 15 , 16 ]. In addition IGF-I receptors play significant role in the integrity and regulation of blood-brain barrier, they have high expression in the cells that constitute it and they facilitate the access of serum IGF-I to entry into the brain[ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Delirium, insulin-like growth factor I, growth hormone in older inpatients

Adamis¹,

Coada²,

Eikelenboom³

et al. 2020

WJP

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BACKGROUND Delirium is a common disorder in elderly medical inpatients with serious adverse outcomes and is characterized by sudden onset, disturbance in attention, awareness, consciousness and cognition, and often with behavioural disturbances. Central to understanding delirium, is understanding mechanisms by which body and brain wellbeing are linked and in particular how brain responses to bodily homeostatic stress is mediated. A number of studies have investigated the relationship between insulin-like growth factor I (IGF-I) and delirium in medically ill hospitalised patients with conflicting results. However, none have investigated growth hormone (GH) which is related to IGF-I via negative feedback. AIM To investigate the relationship between serum levels of IGF-I and GH, and the occurrence of delirium. METHODS Prospective, longitudinal, observational study. Consecutive elderly inpatients (aged 70+), were assessed twice weekly with Montreal cognitive assessment (MoCA), Confusion assessment method (CAM), Acute Physiology and Chronic Health Evaluation II. Delirium was defined using CAM. Previous history of dementia was evaluated with the Informant Questionnaire on Cognitive Decline in the Elderly. IGF-I and GH levels were estimated with the ELISA method. Generalized estimating equations (GEE) model was applied for the first five assessments to analyze those longitudinal data. RESULTS The sample consisted of 198 participants (mean age 80.63 ± 6.81; range 70-97). Of these 92 (46.5%) were females. Eighty six (43.4%) were identified with a history of dementia. Incident or prevalent delirium during hospitalisation was identified with CAM in 40 participants (20.2%). Evaluation of missing values with Little's MCAR test indicated that they were missing completely at random (MCAR χ 2 = 12.24, u : 9, P = 0.20). Using GEE for the analysis we found that low MoCA scores, low levels of IGF-I and high levels of GH were significantly associated with any delirium (prevalence, incident, or fluctuating , during the study period (Wald χ 2 = 12.231; u : 1, P < 0.001, Wald χ 2 = 7.196, u : 1, P = 0.007, Wald χ 2 = 6.210; : u: 1, P = 0.013 respectively). CONCLUSION The results show that low levels of IGF-I, high levels of GH and low scores in cognition are independently associated with the occurrence of any delirium during the hospitalisation of medically ill older people. The results of the study supports the hypothesis that deficits in the immunoreactivity of the brain (low cerebral reserve) may be...

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“…A growing body of evidence suggests AD pathology is driven by metabolic dysfunction (de la Monte and Tong, 2014). Diabetes appears to be an important risk factor for developing AD (Baumgart et al, 2015) with several studies linking diabetes and impaired insulin signaling in the brain to AD pathogenesis (Biessels et al, 2006;Bomfim et al, 2012;Talbot et al, 2012;Zhao et al, 2017;Kim et al, 2019). Overall, diabetics are at a greater risk for AD and the brains of individuals with AD have higher levels of insulin, insulin receptor, and insulin signaling (Hoyer, 2004;Steen et al, 2005;Craft et al, 2013).…”

Section: Metabolism In Admentioning

confidence: 99%

Microglial Immunometabolism in Alzheimer’s Disease

Shippy

Ulland

2020

Front. Cell. Neurosci.

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. In response to Aβ and tau aggregates, microglia, the primary innate immune cells of the central nervous system (CNS), facilitate Aβ and tau clearance and contribute to neuroinflammation that damages neurons. Microglia also perform a wide range of other functions, e.g., synaptic pruning, within the CNS that require a large amount of energy. Glucose appears to be the primary energy source, but microglia can utilize several other substrates for energy production including other sugars and ketone bodies. Recent studies have demonstrated that changes in the metabolic profiles of immune cells, including macrophages, are important in controlling their activation and effector functions. Additional studies have focused on the role of metabolism in neuron and astrocyte function while until recently microglia metabolism has been considerably less well understood. Considering many neurological disorders, such as neurodegeneration associated with AD, are associated with chronic inflammation and alterations in brain energy metabolism, it is hypothesized that microglial metabolism plays a significant role in the inflammatory responses of microglia during neurodegeneration. Here, we review the role of microglial immunometabolism in AD.

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The effects of insulin and insulin-like growth factor I on amyloid precursor protein phosphorylation in in vitro and in vivo models of Alzheimer's disease

Cited by 49 publications

References 111 publications

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

Delirium, insulin-like growth factor I, growth hormone in older inpatients

Microglial Immunometabolism in Alzheimer’s Disease

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