Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?

Stanley, Molly; Macauley, Shannon L.; Holtzman, David M.

doi:10.1084/jem.20160493

Cited by 165 publications

(129 citation statements)

References 86 publications

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“…The topic of amyloidogenesis has been the subject of many scientific endeavors and a great variety of papers have been published, approaching the problem from all possible angles: diagnostics [63][64][65][66], therapeutic [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] and structural/molecular [82][83][84][85]. Our publication does not, however, discuss amyloidogenesis as such, but rather the molecular processes which lead to the formation of fibrillary aggregates commonly referred to as amyloids.…”

Section: Discussionmentioning

confidence: 99%

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Roterman

Banach

Kalinowska

et al. 2016

Entropy

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Abstract:The aqueous environment is a pervasive factor which, in many ways, determines the protein folding process and consequently the activity of proteins. Proteins are unable to perform their function unless immersed in water (membrane proteins excluded from this statement). Tertiary conformational stabilization is dependent on the presence of internal force fields (nonbonding interactions between atoms), as well as an external force field generated by water. The hitherto the unknown structuralization of water as the aqueous environment may be elucidated by analyzing its effects on protein structure and function. Our study is based on the fuzzy oil drop model-a mechanism which describes the formation of a hydrophobic core and attempts to explain the emergence of amyloid-like fibrils. A set of proteins which vary with respect to their fuzzy oil drop status (including titin, transthyretin and a prion protein) have been selected for in-depth analysis to suggest the plausible mechanism of amyloidogenesis.

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Section: Discussionmentioning

confidence: 99%

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Roterman

Banach

Kalinowska

et al. 2016

Entropy

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“…Transport is affected by a number of factors, including obesity, inflammation, glycaemia, diabetes mellitus and levels of circulating triglycerides 39 . In humans, the CSF:serum ratio of insulin levels is reported to be reduced in the presence of whole‑body insulin resistance 40 , as well as with increasing age and in disease states such as AD 41,42 . One possible explanation is decreased transport of insulin across the BBB.…”

Section: Insulin and The Brainmentioning

confidence: 99%

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

et al. 2018

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Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of ‘brain insulin resistance’ and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

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“…Insulin binds to the insulin receptor (IR) on plasma membrane which then auto-phosphorylates and acts as a tyrosine kinase of its downstream insulin receptor substrate 1 (IRS1) [133]. Immediately, the phosphorylated IRS1 triggers a cascade of phosphorylation events on intracellular proteins such as PI3K/Akt, mTOR and S6K to expand the biological response.…”

Section: Major Cancer-related Signaling Pathways With Links To Ad mentioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Alzheimer’s disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated. Hence, we performed a thorough review by summarizing the physiological roles of these key cancer-related signaling pathways in AD pathogenesis, comprising of the crosstalk of these pathways with neurofibrillary tangle and senile plaque formation to impact AD phenotypes. Importantly, the pharmaceutical investigations of anti-aging and AD relevant medications have also been highlighted. In summary, in this review, we discuss the potential role that cancer-related signaling pathways may play in governing the pathogenesis of AD, as well as their potential as future targeted strategies to delay or prevent aging-related diseases and combating AD.

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Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?

Abstract: Stanley and colleagues explore whether changes in insulin levels and insulin signaling are a cause or consequence of AD.

Cited by 165 publications

References 86 publications

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

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