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.

Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 17 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Jing Ma ◽  
Yuan Gao ◽  
Wei Tang ◽  
Wei Huang ◽  
Yong Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Early Stage ◽  
Learning Ability ◽  
Middle Aged ◽  
Protein Levels ◽  
Spine Pathology ◽  
The Impact

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

scholarly journals The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

2013 ◽  
Vol 59 (1) ◽  
pp. 25-50 ◽  
Author(s):  
A.V. Alessenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Role ◽  
Potential Role ◽  
Early Stage ◽  
New Drugs ◽  
Neuronal Function ◽  
Sphingosine 1 Phosphate ◽  
The Brain

The review discusses the functional role of sphingolipids in the pathogenesis of Alzheimer's disease. Certain evidence exist that the imbalance of sphingolipids such as sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate and galactosylceramide in the brain of animals and humans, in the cerebrospinal fluid and blood plasma of patients with Alzheimer's disease play a crucial role in neuronal function by regulating growth, differentiation and cell death in CNS. Activation of sphingomyelinase, which leads to the accumulation of the proapoptotic agent, ceramide, can be considered as a new mechanism for AD and may be a prerequisite for the treatment of this disease by using drugs that inhibit sphingomyelinase activity. The role of sphingolipids as biomarkers for the diagnosis of the early stage of Alzheimer's disease and monitoring the effectiveness of treatment with new drugs is discussed.

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 Involvement of Cholinergic, Adrenergic, and Glutamatergic Network Modulation with Cognitive Dysfunction in Alzheimer’s Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2283
Author(s):  
Yu-Jung Cheng ◽  
Chieh-Hsin Lin ◽  
Hsien-Yuan Lane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Early Stage ◽  
Amyloid Β ◽  
Tau Proteins ◽  
And Oxidative Stress

Alzheimer’s disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. The number of AD cases has been rapidly growing worldwide. Several the related etiological hypotheses include atypical amyloid β (Aβ) deposition, neurofibrillary tangles of tau proteins inside neurons, disturbed neurotransmission, inflammation, and oxidative stress. During AD progression, aberrations in neurotransmission cause cognitive decline—the main symptom of AD. Here, we review the aberrant neurotransmission systems, including cholinergic, adrenergic, and glutamatergic network, and the interactions among these systems as they pertain to AD. We also discuss the key role of N-methyl-d-aspartate receptor (NMDAR) dysfunction in AD-associated cognitive impairment. Furthermore, we summarize the results of recent studies indicating that increasing glutamatergic neurotransmission through the alteration of NMDARs shows potential for treating cognitive decline in mild cognitive impairment or early stage AD. Future studies on the long-term efficiency of NMDA-enhancing strategies in the treatment of AD are warranted.

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.

The potential role of microRNA-146 in Alzheimer’s disease: Biomarker or therapeutic target?

2012 ◽  
Vol 78 (3) ◽  
pp. 398-401 ◽  
Author(s):  
Li-Ling Wang ◽  
Yue Huang ◽  
Gang Wang ◽  
Sheng-Di Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Potential Role ◽  
Disease Biomarker

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 Review of Oxidative Stress Products and Related Genes in Early Alzheimer’s Disease

2021 ◽  
pp. 1-25
Author(s):  
Federica Cioffi ◽  
Rayan Hassan Ibrahim Adam ◽  
Ruchi Bansal ◽  
Kerensa Broersen
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Disease Status ◽  
Diagnostic Value ◽  
Oxidation Products ◽  
Protein Levels ◽  
Stress Levels

Oxidative stress is associated with the progression of Alzheimer’s disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2’-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type 1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients.

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