β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer’s disease

Horré, Katrien; An, Shengli; Vandewyer, Elke; Huang, Yunhong; Ciesielska, Marta; Kloe, Gerdien de; Munck, Sebastian; Strooper, Bart De

doi:10.1186/1750-1326-8-s1-p41

Cited by 27 publications

(37 citation statements)

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“…There is considerable evidence supporting the diverse roles of ARRBs in the pathogenesis of central nervous system diseases, such as ischemia, AD and multiple sclerosis [29][30][31][32][33]. Several recent studies have also implied a role for ARRB2 in PD.…”

Section: Read Full Licensementioning

confidence: 99%

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

Fang

Jiang

et al. 2020

Preprint

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Background Although β-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their function and regulation in Parkinson’s disease (PD) remain poorly defined. Methods We measured expression of ARRB1 and ARRB2 in liposaccharide (LPS)-induced and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. ARRB1-deficient and ARRB2-deficient mouse were used to assess the impact of ARRBs on dopaminergic (DA) neuron loss and microglia activation in PD mouse models. After primary mouse DA neurons were exposed to the conditioned medium from ARRB1 knockdown or ARRB2 knockout microglia stimulated by LPS plus interferon γ (IFN-γ), the degeneration of DA neurons was quantified. Gain- and loss-of-function studies were used to study the effects of ARRBs on microglia activation in vitro. To further understand the mechanism, we measured the activation of classical inflammatory pathways and used RNA sequencing to identify the novel downstream effector of ARRBs. Result In this study, we demonstrate that expression of ARRB1 and ARRB2, particularly in microglia, is reciprocally regulated in PD mouse models. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including DA neuron loss, neuroinflammation and microglia activation in vivo, as well as microglia-mediated neuron damage and inflammation in vitro. In parallel, ARRB1 and ARRB2 produce adverse effects on the activation of inflammatory signal transducers and activators of transcription 1 (STAT1) and nuclear factor-κB (NF-κB) pathways in microglia. We also show that two ARRBs competitively interact with activated p65 in the NF-κB pathway and that nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, is a novel effector acting downstream of both ARRBs. Conclusion Collectively, these data demonstrate that two closely related ARRBs have completely opposite functions in microglia-mediated inflammatory responses, via Nprl3, and differentially affect the pathogenesis of PD, and suggest a potential therapeutic strategy.

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Section: Read Full Licensementioning

confidence: 99%

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

Fang

Jiang

et al. 2020

Preprint

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“…γ-secretase, which increases Aβ production and contributes to the pathogenesis of Alzheimer's disease [14].…”

Section: /4mentioning

confidence: 99%

NTPDase2 as a Surface Marker to Isolate Flow Cytometrically a M�ller Glial Cell Enriched Population from Dissociated Neural Retinae

Hoek¹,

Quinn²,

Alves³

et al. 2018

J Neurosci Neurosurg

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The development of psychotropic has slowed over the last two decades for essentially economic reasons; the drug industry has invested more in the field of oncology and autoimmune diseases. However, there are still avenues to explore, such as allostery for the development of drugs in the field of anxiety depression, bipolarity in particular. Other concepts are suggested in this article as the β-arrestins potential therapeutic targets in Alzheimer's disease (AD), the inhibitors of phosphodiesterase 10A for Huntington's disease, and the epigenetic in schizophrenia, peroxisome proliferator-activated receptors in neurodegenerative diseases.

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“…βsecretase has been characterized as a membrane-bound aspartic protease termed beta-site APP-cleaving enzyme 1 (BACE1), while γ-secretase is a complex comprised of presenilin-1 or -2, nicastrin, anterior pharynx-defective 1 (Aph-1) and presenilin enhancer 2 (Pen-2) [41]. βarrestin 2, is a novel member of the γ-secretase complex that physically associates with the Aph-1α subunit of the γ-secretase complex and redistributes the complex toward detergentresistant membranes, increasing the catalytic activity of the complex [42]. Moreover, β-arrestin 2 expression is elevated in individuals with AD and its overexpression leads to an increase in Aβ peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2-/-mice.…”

Section: Amiloidogenic Processing Of App and Aβ Generationmentioning

confidence: 99%

Free Cholesterol — A Double-Edge Sword in Alzheimer Disease

Fernández‐Checa¹

2015

Alzheimer's Disease - Challenges for the Future

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Additional information is available at the end of the chapter http://dx.doi.org/10.5772/59935 . IntroductionAlzheimer's disease AD is a progressive neurodegenerative disorder that accounts for most of dementia cases in elder people. The main features of AD include a progressive deterioration of intellectual functions, most prominently memory impairment, loss of language ability, and cognitive deficits. Motor defects appear in the late phases of the disease and basic activities of daily living are gradually compromised as the pathology progresses to advanced phases, and are often accompanied by psychosis and agitation [ , ]. The hallmarks of the disease include the accumulation of amyloid-peptide A inside neurons and in the extracellular brain space, and the intracellular formation of neurofibrillary tangles NFTs composed of hyperphosphorylated tau protein, loss of synapses at specific brain sites as well as the degeneration of cholinergic neurons from the basal forebrain [ ]. The prevalence of AD is about % of the population over years of age, which increases -fold every years afterwards [ , ]. This high rate prevalence together with the increase in life expectancy, point to AD as one of the most serious health concerns wordlwide, whose incidence is expected to tiple in the nextdecades unless more effective therapies are available [ ].The identification of new targets for the development of more effective therapeutic approaches requires a better understanding of the molecular pathways leading to AD. In this regard, both genetic and environmental factors are increasingly recognized to contribute to the development of AD, which occurs in two forms. The sporadic form of the disease, which affects people over years of age and accounts for the vast mayority of AD cases. In a small proportion % , the disease is inherited as an autosomal dominant trait and appears as an early onset in people younger than years of age. Mutations within three genes, the amyloid precursor protein APP gene on chromosome , the presenilin PSEN gene on chromosome , and the presenilin PSEN gene on chromosome , have been identified as the main cause of © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.early onset familial AD [ -]. While these findings are key for our understanding of the pathogenesis of familial AD, these mutations account for % of all autosomal dominant early onset cases.In the last years, it has become increasingly recognized that cholesterol plays a significant role in AD. The first evidence of the importance of cholesterol was the discovery that the ε allele of the cholesterol transport protein apolipoprotein E ApoE is associated with a higher risk of developing both familial and sporadic AD and modulates the age of AD onset [ -]. Despite these findings, the impact and causal role of...

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β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer’s disease

Cited by 27 publications

References 0 publications

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

NTPDase2 as a Surface Marker to Isolate Flow Cytometrically a M�ller Glial Cell Enriched Population from Dissociated Neural Retinae

Free Cholesterol — A Double-Edge Sword in Alzheimer Disease

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