Cholesterol retention in Alzheimer's brain is responsible for high β- and γ-secretase activities and Aβ production

Xiong, Huaqi; Callaghan, Debbie; Jones, Aimee; Walker, Douglas G.; Lue, Lih‐Fen; Beach, Thomas G.; Sue, Lucia I.; Woulfe, John; Xu, Huaxi; Stanimirovic, Danica; Zhang, Wandong

doi:10.1016/j.nbd.2007.10.005

Cited by 245 publications

(215 citation statements)

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“…The prevalence of the disorder is increasing at an alarming rate, afflicting *30 million people worldwide and is expected to quadruple by 2050 [2]. The neuropathological characteristics of AD include the presence of senile plaques, defective brain insulin signaling [3], dysregulated cholesterol homeostasis [4], decreased glucose utilization, increased oxidative stress, and inflammation leading to neurodegeneration [5]. The plaques are composed mostly of aggregated amyloid-b 40 (Ab 40 ) and Ab 42 peptides, which are derived by proteolysis of the amyloid-b precursor protein (AbPP) [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

et al. 2016

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Section: Introductionmentioning

confidence: 99%

“…Another recognized feature of AD is the dysregulation of cholesterol and lipid homeostasis in the brain [4]. Such dysregulation may increase Ab production [4], and several studies have linked cholesterol, lipid, and lipoprotein dysregulation to the insulin-resistant state [27].…”

Section: Introductionmentioning

confidence: 99%

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

et al. 2016

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“…The regulated activity of these receptors has a widespread effect on multiple aspects of development. For example, in mammals, they regulate cholesterol, osteoclast differentiation and triglyceride metabolism, and their impaired function leads to cardiovascular, bone, metabolic, and, possibly, Alzheimer's diseases (Patel and Forman 2004; Beaven and Tontonoz 2006;Mark et al 2006;Robertson et al 2006;Xiong et al 2008;Spyridon et al 2011 The EcR gene of Drosophila produces three protein isoforms (EcRA, EcRB1, and EcRB2) by using two promoters and alternative splicing (Talbot et al 1993). The three isoforms are able to heterodimerize USP and share the same carboxy terminus, which includes the hormone-binding and DNA-binding domains, while the amino termini are unique to each isoform.…”

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Isoform-Specific Regulation of a Steroid Hormone Nuclear Receptor by an E3 Ubiquitin Ligase inDrosophila melanogaster

2011

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The steroid hormone 20-hydroxyecdysone (20E) regulates gene transcription through the heterodimeric nuclear receptor composed of ecdysone receptor (EcR) and Ultraspiracle (USP). The EcR gene encodes three protein isoforms-A, B1, and B2-with variant N-terminal domains that mediate tissue and developmental stage-specific responses to 20E. Ariadne-1a is a conserved member of the RING finger family of ubiquitin ligases first identified in Drosophila melanogaster. Loss-of-function mutations at key cysteines in either of the two RING finger motifs, as well as general overexpression of this enzyme, cause lethality in pupae, which suggests a requirement in metamorphosis. Here, we show that Ariadne-1a binds specifically the isoform A of EcR and ubiquitylates it. Coimmunoprecipitation experiments indicate that the full sequence of EcRA is required for this binding. Protein levels of EcRA and USP change in opposite directions when those of ARI-1a are genetically altered. This is an isoform-specific, E3-dependent regulatory mechanism for a steroid nuclear receptor. Further, qRT-PCR experiments show that the ARI-1a levels lead to the transcriptional regulation of Eip78C, Eip74EF, Eip75B, and Br-C, as well as that of EcR and usp genes. Thus, the activity of this enzyme results in the regulation of dimerizing receptors at the protein and gene transcription levels. This fine-tuned orchestration by a conserved ubiquitin ligase is required during insect metamorphosis and, likely, in other steroid hormone-controlled processes across species. STEROID hormones regulate multiple processes during development and adult life. In Drosophila, the steroid hormone 20-hydroxyecdysone (20E) triggers the transcriptional changes required for gonad development, larval molting, and the onset and completion of metamorphosis (Sliter and Gilbert 1992;Henrich et al. 1993;Carney and Bender 2000;Riddiford et al. 2000; Beckstead et al. 2005). Differentiation of imaginal structures and neuronal remodeling, two major features of metamorphosis, have been used as cellular systems to analyze the functional role of proteins that elicit morphogenetic changes at this phase of the life cycle (Schubiger et al. 2005;Brown et al. 2006;Santos et al. 2006). 20E regulates gene expression by binding to its nuclear receptor, EcR (King-Jones and Thummel 2005). To bind 20E and stimulate transcription, however, EcR must heterodimerize with Ultraspiracle (USP) to reconstitute specific activation domains (Yao et al. 1992). Different 20E levels activate transcription of different sets of genes (Champlin and Truman 1998;Li and White 2003;Schubiger et al. 2003). Like their vertebrate cognates (Chen and Evans 1995), unliganded EcR and USP act as repressors of transcription, whereas the liganded receptor stimulates expression of target genes (Tsai et al. 1999;Ghbeish et al. 2001;Schubiger et al. 2003).On the basis of sequence identities, it is considered that the mammalian orthologs of EcR are the group H of nuclear receptor subfamily 1 that include LXR and FXR, while US...

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“…AD brain had significant cholesterol retention and high β-and γ-secretase activities as compared to age matched non-demented controls. β-and γ-secretase activities were highly stimulated by 40 μm of cholesterol in the lysate of AD brain (Xiong et al, 2008). Thus, enhanced cholesterol level may promote the enzyme activities of β-and γ-secretases, thereby accelerating the amyloidogenic processing of APP, resulting in the increased accumulation and deposition of Aβ in AD patients.…”

Section: Lipid Changes Related To Amyloid β-Induced Ad Pathologymentioning

confidence: 99%

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

Xiang

Lam

Shui

2015

Biological Chemistry

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Lipids serve many distinct functions in cellular homeostasis such as membrane organization, as a platform for membrane function and protein/protein or protein/lipid interaction, energy storage, as well as secondary messengers in signal transduction. Perturbations in lipid homeostasis may result in abnormal cellular function. Alzheimer's disease (AD) is a neurodegenerative disorder in which the brain represents the primary site of pathology. While there is a plethora of previous work pertaining to AD pathogenesis, the precise mechanism of the disease is still not well-understood. Recent waves of technological advances in the realm of lipidomics have enabled scientists to look at AD pathogenesis from a previously unexplored perspective, and studies have revealed extensive lipid aberrations are implicated in the disease pathology. Herein, we review the critical lipids alternations, which affect amyloid plaque and neurofibrillary tangles formation and accumulation, as well as lipid aberrations related to neuronal and synaptic dysfunction in cells and animal models. We also summarize lipid abnormalities observed in the human cerebrospinal fluid (CSF), as well as other circulating fluids including plasma and serum in association with AD, which could serve as candidate biomarkers to diagnose and monitor the disease.

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Cholesterol retention in Alzheimer's brain is responsible for high β- and γ-secretase activities and Aβ production

Cited by 245 publications

References 60 publications

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

Isoform-Specific Regulation of a Steroid Hormone Nuclear Receptor by an E3 Ubiquitin Ligase inDrosophila melanogaster

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

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