scholarly journals RCAN1 Inhibits BACE2 Turnover by Attenuating Proteasome-Mediated BACE2 Degradation

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Kaixin Qiu ◽  
Shuai Wang ◽  
Xin Wang ◽  
Fengting Wang ◽  
Yili Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein A ◽  
Potential Mechanism ◽  
Neuritic Plaques ◽  
Protein Levels ◽  
Bace1 Expression ◽  
Main Component

Amyloid-β protein (Aβ) is the main component of neuritic plaques, the pathological hallmark of Alzheimer’s disease (AD). β-site APP cleaving enzyme 1 (BACE1) is a major β-secretase contributing to Aβ generation. β-site APP cleaving enzyme 2 (BACE2), the homolog of BACE1, is not only a θ-secretase but also a conditional β-secretase. Previous studies showed that regulator of calcineurin 1 (RCAN1) is markedly increased by AD and promotes BACE1 expression. However, the role of RCAN1 in BACE2 regulation remains elusive. Here, we showed that RCAN1 increases BACE2 protein levels. Moreover, RCAN1 inhibits the turnover of BACE2 protein. Furthermore, RCAN1 attenuates proteasome-mediated BACE2 degradation, but not lysosome-mediated BACE2 degradation. Taken together, our work indicates that RCAN1 inhibits BACE2 turnover by attenuating proteasome-mediated BACE2 degradation. It advances our understanding of BACE2 regulation and provides a potential mechanism of BACE2 dysregulation in AD.

scholarly journals Elevated CLOCK and BMAL1 Contribute to the Impairment of Aerobic Glycolysis from Astrocytes in Alzheimer’s Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 7862
Author(s):  
Ik Dong Yoo ◽  
Min Woo Park ◽  
Hyeon Woo Cha ◽  
Sunmi Yoon ◽  
Napissara Boonpraman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Over Expression ◽  
Protein Levels ◽  
Human Astrocytes ◽  
Altered Glucose

Altered glucose metabolism has been implicated in the pathogenesis of Alzheimer’s disease (AD). Aerobic glycolysis from astrocytes is a critical metabolic pathway for brain energy metabolism. Disturbances of circadian rhythm have been associated with AD. While the role of circadian locomotor output cycles kaput (CLOCK) and brain muscle ARNT-like1 (BMAL1), the major components in the regulation of circadian rhythm, has been identified in the brain, the mechanism by which CLOCK and BMAL1 regulates the dysfunction of astrocytes in AD remains unclear. Here, we show that the protein levels of CLOCK and BMAL1 are significantly elevated in impaired astrocytes of cerebral cortex from patients with AD. We demonstrate that the over-expression of CLOCK and BMAL1 significantly suppresses aerobic glycolysis and lactate production by the reduction in hexokinase 1 (HK1) and lactate dehydrogenase A (LDHA) protein levels in human astrocytes. Moreover, the elevation of CLOCK and BMAL1 induces functional impairment by the suppression of glial fibrillary acidic protein (GFAP)-positive filaments in human astrocytes. Furthermore, the elevation of CLOCK and BMAL1 promotes cytotoxicity by the activation of caspase-3-dependent apoptosis in human astrocytes. These results suggest that the elevation of CLOCK and BMAL1 contributes to the impairment of astrocytes by inhibition of aerobic glycolysis in AD.

scholarly journals Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution

2014 ◽  
Vol 51 (3) ◽  
pp. 1206-1220 ◽  
Author(s):  
C. Vergara ◽  
L. Ordóñez-Gutiérrez ◽  
F. Wandosell ◽  
I. Ferrer ◽  
J. A. del Río ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Disease Evolution ◽  
Protein Levels

Low Dose Pioglitazone Attenuates Oxidative Damage in Early Alzheimer's Disease by Binding mitoNEET

2015 ◽  
Vol 5 (1) ◽  
pp. 24-45 ◽  
Author(s):  
Charles D. Hammack ◽  
George Perry ◽  
Richard G. LeBaron ◽  
Greg Villareal ◽  
Clyde F. Phelix
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Damage ◽  
Low Dose ◽  
Mitochondrial Protein ◽  
Central Component ◽  
Protein Levels ◽  
Early Alzheimer’S Disease ◽  
Peroxiredoxin 3

Oxidative damage (OD) is considered to be a central component in the progression of Alzheimer's disease (AD). 8-hydroxyguanosine (8-OHG), a readily oxidized ribonucleic acid found in AD, was used as a biomarker to investigate the role of OD in the progression of the disease. A disruption in two critical Thioredoxin-Dependent Peroxiredoxin System components, peroxiredoxin-3 (Prx-3) and thioredoxin (Trx), may serve as a source of the increased accumulation of OD observed in AD. We demonstrate that OD, in the form of 8-OHG, was quantitatively most significant during the earliest stage of AD [F (3, 25) = 5.08, p < .01]. A drastic decline in mitochondrial protein levels of Prx-3 [F (3, 25) = 8.74, p. < 01] and Trx [F (3, 25) = 4.33, p. < 05] were also observed across the progression of the disease. We then tested the efficacy of pioglitazone, a thiazolidinedione class drug aimed to delay onset of AD by acting on mitoNEET. Our results showed a significant reduction in the oxidized variant of mitoNEET within the incipient population when a 0.8mg dose was simulated in silico (p = 0.0242; a. < 05).

scholarly journals Exercise-mediated alteration of hippocampal Dicer mRNA and miRNAs is associated with lower BACE1 gene expression and Aβ1-42 in female 3xTg-AD mice

2020 ◽  
Vol 124 (6) ◽  
pp. 1571-1577
Author(s):  
Cory M. Dungan ◽  
Taylor Valentino ◽  
Ivan J. Vechetti ◽  
Christopher J. Zdunek ◽  
Michael P. Murphy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mirna Expression ◽  
Potential Mechanism ◽  
Beneficial Effects ◽  
Bace1 Expression

Previous studies have outlined the beneficial effects of exercise on lowering BACE1 expression and reducing Aβ plaques. This study extends upon the work of others by outlining a new potential mechanism by which exercise elicits beneficial effects on Alzheimer’s disease pathology, specifically through modulation of Dicer and miRNA expression. This is the first study to examine Dicer and miRNA expression in the hippocampus of the 3xTg model within the context of exercise.

scholarly journals BACE1 Inhibition Using 2’-OMePS Steric Blocking Antisense Oligonucleotides

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 705
Author(s):  
Chakravarthy ◽  
Veedu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Antisense Oligonucleotides ◽  
Precursor Protein ◽  
Exon 2 ◽  
Protein Levels ◽  
Bace1 Expression ◽  
Beta Peptide ◽  
Bace1 Inhibition

Amyloid beta-peptide is produced by the cleavage of amyloid precursor protein by two secretases, a β-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and a γ-secretase. It has been hypothesised that partial inhibition of BACE1 in individuals with a high risk of developing Alzheimer’s disease may be beneficial in preventing cognitive decline. In this study, we report the development of a novel antisense oligonucleotide (AO) that could efficiently downregulate the BACE1 transcript and partially inhibit BACE1 protein. We designed and synthesised a range of 2’-OMethyl-modified antisense oligonucleotides with a phosphorothioate backbone across various exons of the BACE1 transcript, of which AO2, targeting exon 2, efficiently downregulated BACE1 RNA expression by 90%. The sequence of AO2 was later synthesised with a phosphorodiamidate morpholino chemistry, which was found to be not as efficient at downregulating BACE1 expression as the 2’-OMethyl antisense oligonucleotides with a phosphorothioate backbone variant. AO2 also reduced BACE1 protein levels by 45%. In line with our results, we firmly believe that AO2 could be used as a potential preventative therapeutic strategy for Alzheimer’s disease.

scholarly journals Candidate Alzheimer’s Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression

2021 ◽  
Vol 22 (7) ◽  
pp. 3653
Author(s):  
Siranjeevi Nagaraj ◽  
Andrew Want ◽  
Katarzyna Laskowska-Kaszub ◽  
Aleksandra Fesiuk ◽  
Sara Vaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Erk Pathway ◽  
Neurofibrillary Pathology ◽  
Protein Levels ◽  
Disease Biomarker ◽  
Extracellular Signal ◽  
Novel Target

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer’s disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer’s disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.

Effects of altered RTN3 expression on BACE1 activity and Alzheimer’s neuritic plaques

2017 ◽  
Vol 28 (2) ◽  
pp. 145-154 ◽  
Author(s):  
Md Golam Sharoar ◽  
Riqiang Yan
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Neuritic Plaques ◽  
Amyloid Peptides ◽  
Protein Levels ◽  
Bace1 Expression ◽  
Β Amyloid ◽  
Tubular Endoplasmic Reticulum ◽  
Bace1 Activity

AbstractReticulon 3 (RTN3), which is a member of the reticulon family of proteins, has a biochemical function of shaping tubular endoplasmic reticulum. RTN3 has also been found to interact with β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which initiates the generation of β-amyloid peptides (Aβ) from amyloid precursor protein. Aβ is the major proteinaceous component in neuritic plaques, which constitute one of the major pathological features in brains of Alzheimer’s disease (AD) patients. Mice deficient in or overexpressing RTN3 have altered amyloid deposition through effects on BACE1 expression and activity. In this review, we will summarize the current findings concerning the role of RTN3 in AD pathogenesis and demonstrate that RTN3 protein levels act as age-dependent modulators of BACE1 activity and Aβ deposition during the pathogenic progression of AD.

scholarly journals Flotillin: A Promising Biomarker for Alzheimer’s Disease

2020 ◽  
Vol 10 (2) ◽  
pp. 20 ◽  
Author(s):  
Efthalia Angelopoulou ◽  
Yam Nath Paudel ◽  
Mohd. Farooq Shaikh ◽  
Christina Piperi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Rafts ◽  
Protein Interactions ◽  
Tau Protein ◽  
Clinical Evidence ◽  
Senile Plaques ◽  
App Processing ◽  
Protein Levels

Alzheimer’s disease (AD) is characterized by the accumulation of beta amyloid (Aβ) in extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) mainly consisting of tau protein. Although the exact etiology of the disease remains elusive, accumulating evidence highlights the key role of lipid rafts, as well as the endocytic pathways in amyloidogenic amyloid precursor protein (APP) processing and AD pathogenesis. The combination of reduced Aβ42 levels and increased phosphorylated tau protein levels in the cerebrospinal fluid (CSF) is the most well established biomarker, along with Pittsburgh compound B and positron emission tomography (PiB-PET) for amyloid imaging. However, their invasive nature, the cost, and their availability often limit their use. In this context, an easily detectable marker for AD diagnosis even at preclinical stages is highly needed. Flotillins, being hydrophobic proteins located in lipid rafts of intra- and extracellular vesicles, are mainly involved in signal transduction and membrane–protein interactions. Accumulating evidence highlights the emerging implication of flotillins in AD pathogenesis, by affecting APP endocytosis and processing, Ca2+ homeostasis, mitochondrial dysfunction, neuronal apoptosis, Aβ-induced neurotoxicity, and prion-like spreading of Aβ. Importantly, there is also clinical evidence supporting their potential use as biomarker candidates for AD, due to reduced serum and CSF levels that correlate with amyloid burden in AD patients compared with controls. This review focuses on the emerging preclinical and clinical evidence on the role of flotillins in AD pathogenesis, further addressing their potential usage as disease biomarkers.

scholarly journals Hypertension and Alzheimer’s disease: indirect effects through circle of Willis atherosclerosis

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Graham M L Eglit ◽  
Alexandra J Weigand ◽  
Daniel A Nation ◽  
Mark W Bondi ◽  
Katherine J Bangen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Indirect Effects ◽  
Arterial Wall ◽  
Circle Of Willis ◽  
Cerebral Hypoperfusion ◽  
Vascular Risk ◽  
Neuritic Plaques ◽  
Continuous Measures

Abstract Hypertension is common among older adults and is believed to increase susceptibility to Alzheimer’s disease, but mechanisms underlying this relationship are unclear. Hypertension also promotes circle of Willis atherosclerosis, which contributes to cerebral hypoperfusion and arterial wall stiffening, two potential mechanisms linking hypertension to Alzheimer’s disease. To examine the role of circle of Willis atherosclerosis in the association between hypertension and Alzheimer’s disease neuropathology, we analysed post-mortem neuropathological data on 2198 decedents from the National Alzheimer’s Coordinating Center database [mean (standard deviation) age at last visit 80.51 (1.95) and 47.1% female] using joint simultaneous (i.e. mediation) modelling. Within the overall sample and among Alzheimer’s dementia decedents, hypertension was indirectly associated with increased neuritic plaques and neurofibrillary tangles through its association with circle of Willis atherosclerosis. Similar indirect effects were observed for continuous measures of systolic and diastolic blood pressure. These results suggest that hypertension may promote Alzheimer’s disease pathology indirectly through intracranial atherosclerosis by limiting cerebral blood flow and/or dampening perivascular clearance. Circle of Willis atherosclerosis may be an important point of convergence between vascular risk factors, cerebrovascular changes and Alzheimer’s disease neuropathology.

scholarly journals Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 58
Author(s):  
Enes Akyuz ◽  
Chiara Villa ◽  
Merve Beker ◽  
Birsen Elibol
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Kir Channels ◽  
Protein Levels ◽  
Model Of Alzheimer’S Disease ◽  
Inwardly Rectifying

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology and characterized by cognitive deficits and memory loss. The pathogenesis of AD is not yet completely elucidated, and no curative treatment is currently available. Inwardly rectifying potassium (Kir) channels are important for playing a key role in maintaining the resting membrane potential and controlling cell excitability, being largely expressed in both excitable and non-excitable tissues, including neurons. Accordingly, the aim of the study is to investigate the role of neuronal Kir channels in AD pathophysiology. The mRNA and protein levels of neuronal Kir2.1, Kir3.1, and Kir6.2 were evaluated by real-time PCR and Western blot analysis from the hippocampus of an amyloid-β(Aβ)(1-42)-infused rat model of AD. Extracellular deposition of Aβ was confirmed by both histological Congo red staining and immunofluorescence analysis. Significant decreased mRNA and protein levels of Kir2.1 and Kir6.2 channels were observed in the rat model of AD, whereas no differences were found in Kir3.1 channel levels as compared with controls. Our results provide in vivo evidence that Aβ can modulate the expression of these channels, which may represent novel potential therapeutic targets in the treatment of AD.

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