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 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 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

scholarly journals A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer’s Disease

2022 ◽  
Vol 23 (1) ◽  
pp. 504
Author(s):  
Xuemin Peng ◽  
Rongping Fan ◽  
Lei Xie ◽  
Xiaoli Shi ◽  
Kun Dong ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Light Therapy

Type 2 diabetes mellitus (T2DM) patients are at a higher risk of developing Alzheimer’s disease (AD). Mounting evidence suggests the emerging important role of circadian rhythms in many diseases. Circadian rhythm disruption is considered to contribute to both T2DM and AD. Here, we review the relationship among circadian rhythm disruption, T2DM and AD, and suggest that the occurrence and progression of T2DM and AD may in part be associated with circadian disruption. Then, we summarize the promising therapeutic strategies targeting circadian dysfunction for T2DM and AD, including pharmacological treatment such as melatonin, orexin, and circadian molecules, as well as non-pharmacological treatments like light therapy, feeding behavior, and exercise.

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 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.

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 Circadian Rhythm Disruption and Alzheimer’s Disease: The Dynamics of a Vicious Cycle

2020 ◽  
Vol 19 (2) ◽  
pp. 248-264 ◽  
Author(s):  
Ashish Sharma ◽  
Gautam Sethi ◽  
Murtaza M. Tambuwala ◽  
Alaa A. A. Aljabali ◽  
Dinesh Kumar Chellappan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Circadian Clock ◽  
Mammalian Cells ◽  
Bright Light ◽  
Light Therapy ◽  
Vicious Cycle ◽  
Clock Proteins

: All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, CLOCK, BMAL1, ROR, and clock-controlled proteins like AVP, SIRT1, FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated.

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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