Cholesterol‐induced astrocyte activation is associated with increased amyloid precursor protein expression and processing

Ávila-Muñoz, Evangelina; Arias, Clorinda

doi:10.1002/glia.22874

Cited by 31 publications

(28 citation statements)

References 68 publications

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“…The levels of APP holoproteins, including the isoform containing KPI-domain known to be expressed mostly in astrocytes, are increased time-dependently following U18666A treatment. This is consistent with a recent study which showed that increasing concentrations of cholesterol in the culture media can trigger cholesterol accumulation and elevate APP levels in astrocytes (Avila-Muñoz & Arias, 2015).…”

Section: Discussionsupporting

confidence: 93%

“…The levels of APP holoproteins, including the isoform containing KPI‐domain known to be expressed mostly in astrocytes, are increased time‐dependently following U18666A treatment. This is consistent with a recent study which showed that increasing concentrations of cholesterol in the culture media can trigger cholesterol accumulation and elevate APP levels in astrocytes (Avila‐Muñoz & Arias, ). There is also evidence that APP levels are increased in reactive astrocytes in the affected brain regions of NPC1 knockout mice—characterized by intracellular accumulation of cholesterol in many tissues including the brain (Kodam et al, ).…”

Section: Discussionsupporting

confidence: 93%

“…Accompanying APP, we observed an elevated level of a-/b-CTFs and secretory levels of soluble APP in U18666A-treated astrocytes. This is supported by a study which showed an increased concentration of cholesterol in cultured media can enhance b-CTF levels in astrocytes (Avila-Muñoz & Arias, 2015). However, earlier studies using cultured neurons/cell lines revealed that U18666A treatment can lead to either an increase in a-/b-CTFs (Boland et al, 2010;Jin et al, 2004) or an increase in a-CTF and decrease in b-CTF (Davis, 2008;Runz et al, 2002) levels.…”

Section: Discussionmentioning

confidence: 86%

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Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Yang

Wang

Kar

2017

Glia

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Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play an important role in the degeneration of neurons and development of Alzheimer's disease (AD). Current evidence indicates that high levels of cholesterol-which increase the risk of developing AD-can influence Aβ production in neurons. However, it remains unclear how altered level/subcellular distribution of cholesterol in astrocytes can influence APP metabolism. In this study, we evaluated the effects of cholesterol transport inhibitor U18666A-a class II amphiphile that triggers redistribution of cholesterol within the endosomal-lysosomal (EL) system-on APP levels and metabolism in rat primary cultured astrocytes. Our results revealed that U18666A increased the levels of the APP holoprotein and its cleaved products (α-/β-/η-CTFs) in cultured astrocytes, without altering the total levels of cholesterol or cell viability. The cellular levels of Aβ were also found to be markedly increased, while secretory levels of Aβ were decreased in U18666A-treated astrocytes. We further report a corresponding increase in the activity of the enzymes regulating APP processing, such as α-secretase, β-secretase, and γ-secretase as a consequence of U18666A treatment. Additionally, APP-cleaved products are partly accumulated in the lysosomes following cholesterol sequestration within EL system possibly due to decreased clearance. Interestingly, serum delipidation attenuated enhanced levels of APP and its cleaved products following U18666A treatment. Collectively, these results suggest that cholesterol sequestration within the EL system in astrocytes can influence APP metabolism and the accumulation of APP-cleaved products including Aβ peptides, which can contribute to the development of AD pathology.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 86%

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Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Yang

Wang

Kar

2017

Glia

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“…Nevertheless, the stimulus‐dependent capacity of reactive astrocytes to express APP (Avila‐Muñoz & Arias, ; Siman, Card, Nelson, & Davis, ) as well as the APP processing enzyme BACE1 (Hartlage‐Rübsamen et al, ) and components of the γ‐secretase complex (Nadler et al, ) indicate a potential astrocytic contribution to amyloid pathology. Indeed, intracellular Abeta was detected in astrocytes of AD cortex (Akiyama et al, ).…”

Section: Discussionmentioning

confidence: 99%

Defined astrocytic expression of human amyloid precursor protein in Tg2576 mouse brain

Heiland

Zeitschel

Puchades

et al. 2018

Glia

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Transgenic Tg2576 mice expressing human amyloid precursor protein (hAPP) with the Swedish mutation are among the most frequently used animal models to study the amyloid pathology related to Alzheimer's disease (AD). The transgene expression in this model is considered to be neuron‐specific. Using a novel hAPP‐specific antibody in combination with cell type‐specific markers for double immunofluorescent labelings and laser scanning microscopy, we here report that—in addition to neurons throughout the brain—astrocytes in the corpus callosum and to a lesser extent in neocortex express hAPP. This astrocytic hAPP expression is already detectable in young Tg2576 mice before the onset of amyloid pathology and still present in aged Tg2576 mice with robust amyloid pathology in neocortex, hippocampus, and corpus callosum. Surprisingly, hAPP immunoreactivity in cortex is restricted to resting astrocytes distant from amyloid plaques but absent from reactive astrocytes in close proximity to amyloid plaques. In contrast, neither microglial cells nor oligodendrocytes of young or aged Tg2576 mice display hAPP labeling. The astrocytic expression of hAPP is substantiated by the analyses of hAPP mRNA and protein expression in primary cultures derived from Tg2576 offspring. We conclude that astrocytes, in particular in corpus callosum, may contribute to amyloid pathology in Tg2576 mice and thus mimic this aspect of AD pathology.

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“…Arias [36] in isolated astrocytes obtained from brain cortex of 1-to 3-day-old Wistar rats, they found astrocyte activation, An increase on the expression of amyloid precursor protein (APP), and promoted its amyloidogenic processing, and an increase in reactive species oxygen (ROS), a marker of oxidative stress, after treating the culture for 48 h with cholesterol concentrated at 25 or 50 μM. All these parameters measured, including glia activation, resemble features that have been found in postmortem brain tissues obtained from AD patients [37][38][39], but how the consumption of a diet high in cholesterol can contribute to the development of AD?…”

Section: Impact Of a Diet Rich In Cholesterol Or Fat On The Developmementioning

confidence: 99%

High-Fat and Cholesterol Intake Affects Brain Homeostasis and Could Accelerate the Development of Dementia: A Systemic View

Meraz-Ríos¹,

Leal-Galicia²

2016

Update on Dementia

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Alzheimer's disease is the most common type of dementia in occidental countries. The majority of the cases develop the disease for no genetic reasons; therefore, it is crucial to establish which environmental factors trigger the development of the disease. It has been proposed that nutritional habits, especially main components of Western countries' diet such as saturated fat or cholesterol, increase the risk for development of Alzheimer's disease (AD) and/or accelerate the onset of the disease, which is a big concern in countries where obesity is a public health problem. It is crucial to understand the links between alimentary habits and the development of AD and other types of dementia. A possible mechanism is the disruption of blood-brain barrier (BBB), which is the protection of the brain from circulating blood. Such disruptions can result from consuming high-fat diet (HFD) or high-cholesterol diet (HCD) and inflammation produced by alteration in brain vasculature resulted for chronic consumption of such type of diets. What has named a "Systemic view" comprises the idea that; what happens outside of the brain environment does affect brain functioning and the modifications experienced in the brain environment resulted from the influence of external factors will affect the entire body. In the current chapter, we will review the state of the art in the studies of the impact of a diet rich in fat or cholesterol on the brain and how the alterations induced in other organs can impact brain functioning increasing the susceptibility of development of dementia.

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Cholesterol‐induced astrocyte activation is associated with increased amyloid precursor protein expression and processing

Cited by 31 publications

References 68 publications

Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Defined astrocytic expression of human amyloid precursor protein in Tg2576 mouse brain

High-Fat and Cholesterol Intake Affects Brain Homeostasis and Could Accelerate the Development of Dementia: A Systemic View

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