27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation

Ismail, Muhammad-Al-Mustafa; Mateos, Laura; Maioli, Silvia; Merino‐Serrais, Paula; Ali, Zeina; Lodeiro, María F.; Westman, Eric; Leitersdorf, Eran; Gulyás, Balázs; Wahlund, Lars‐Olof; Winblad, Bengt; Savitcheva, Irina; Björkhem, Ingemar; Cedazo-Mı́nguez, Ángel

doi:10.1084/jem.20160534

Cited by 70 publications

(88 citation statements)

References 67 publications

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“…These animals also show cognitive impairment at 12 months old together with reduced glucose uptake in the brain . The mechanisms leading to reduced glucose uptake in these mice is mediated by an over‐activation of the RAS system, leading to an imbalance between the angiotensin isoforms AngIII and IV . The balance between these forms is also modified by the catabolism of AngIV by aminopeptidases, which are modulated importantly by 27‐OH, particularly aminopeptidase‐A (AP‐A) and aminopeptidase‐N (AP‐N).…”

Section: Different Treatment Approaches Based On Pathogenesismentioning

confidence: 99%

Current and emerging avenues for Alzheimer's disease drug targets

et al. 2019

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Loera-Valencia R, Cedazo-Minguez A, ). Current and emerging avenues for Alzheimer's disease drug targets (Review). J Intern Med 2019; 286: 398-437.Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Ab) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Ab and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy. ReviewInsoluble Ab fibrils are taken into consideration as the main responsible for spine pathology. On the other hand, in both transgenic mouse models of AD and human AD brain, synapse defects and memory loss correlate weakly with the presence of Ab Current and novel Alzheimer´s disease therapy targets / R. Loera-Valencia et al.

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Section: Different Treatment Approaches Based On Pathogenesismentioning

confidence: 99%

Current and emerging avenues for Alzheimer's disease drug targets

et al. 2019

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“…Cholesterol was proven to cause disturbance of the neurovascular unit which results in impaired clearance of Aβ , disruption of BBB function and impairment in cerebral blood flow . It also promoted central insulin resistance in mice fed with high‐cholesterol diet , whilst reduced glucose uptake into the brain was observed in mice with chronically elevated levels of 27‐OHC .…”

Section: The Role Of Cholesterol In Neurodegenerationmentioning

confidence: 99%

“…The activation of GLUT4 promotes glucose uptake in hippocampal neurons . Modulation of IRAP is influenced by the balance in counteracting effects of Ang III (IRAP activator/GLUT4 inhibitor) and Ang IV (IRAP inhibitor/GLUT4 activator) .…”

Section: The Brain Renin–angiotensin Systemmentioning

confidence: 99%

“…They are autonomous from their systemic counterparts and share important interconnections with each other and with the amyloidogenic and nonamyloidogenic pathways . Moreover, those two systems are involved in central glucose metabolism, cerebral blood flow regulation, neuroinflammation and oxidative stress . The brain RAS participates in memory, although its effects are poorly understood, and overactivation of the central RAS has been demonstrated in early stages of cognitive decline .…”

Section: Introductionmentioning

confidence: 99%

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Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

et al. 2018

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Petek B, Sweden; S€ odersjukhuset, Stockholm, Sweden). Connecting the brain cholesterol and reninangiotensin systems: potential role of statins and RAS-modifying medications in dementia (Review). J Intern Med 2018;284: 620-642.Millions of people worldwide receive agents targeting the renin-angiotensin system (RAS) to treat hypertension or statins to lower cholesterol. The RAS and cholesterol metabolic pathways in the brain are autonomous from their systemic counterparts and are interrelated through the cholesterol metabolite 27-hydroxycholesterol (27-OHC). These systems contribute to memory and dementia pathogenesis through interference in the amyloid-beta cascade, vascular mechanisms, glucose metabolism, apoptosis, neuroinflammation and oxidative stress. Previous studies examining the relationship between these treatments and cognition and dementia risk have produced inconsistent results. Defining the blood-brain barrier penetration of these medications has been challenging, and the mechanisms of action on cognition are not clearly established. Potential biases are apparent in epidemiological and clinical studies, such as reverse epidemiology, indication bias, problems defining medication exposure, uncertain and changing doses, and inappropriate grouping of outcomes and medications. This review summarizes current knowledge of the brain cholesterol and RAS metabolism and the mechanisms by which these pathways affect neurodegeneration. The putative mechanisms of action of statins and medications inhibiting the RAS will be examined, together with prior clinical and animal studies on their effects on cognition. We review prior epidemiological studies, analysing their strengths and biases, and identify areas for future research. Understanding the pathophysiology of the brain cholesterol system and RAS and their links to neurodegeneration has enormous potential. In future, well-designed epidemiological studies could identify potential treatments for Alzheimer's disease (AD) amongst medications that are already in use for other indications.2 Promotion of oxidative stress by acting on LRX in astroglia [90,91].Brain cholesterol and RAS in dementia / B. Petek et al.

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“…Thus, high plasma cholesterol leads to high plasma levels of 27‐hydroxycholesterol and increased flux of this oxysterol into the brain. Increased flux of 27‐hydroxycholesterol into the brain leads to a number of negative effects including reduced uptake of glucose by the brain , reduced levels of the ‘memory protein’ Arc (activity regulated cytoskeleton associated protein) in hippocampus , negative effects on spatial memory, and upregulation of the brain renin–angiotensin system . Patients with Alzheimer′s disease have an accumulation of 27‐hydroxycholesterol in the brain , although we do not know with certainty if this accumulation is a primary process or secondary to the neuronal degeneration.…”

Section: Hypocholesterolaemia and Brain Functionmentioning

confidence: 99%