scholarly journals Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1261
Author(s):  
Laura D’Andrea ◽  
Ramona Stringhi ◽  
Monica Di Luca ◽  
Elena Marcello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Hyperphosphorylated Tau Protein ◽  
Ε4 Allele ◽  
Therapeutic Tools

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.

scholarly journals Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?

2019 ◽  
Vol 20 (3) ◽  
pp. 558 ◽  
Author(s):  
Yuan Dong ◽  
Xiaoheng Li ◽  
Jinbo Cheng ◽  
Lin Hou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Tau Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Cognitive Changes ◽  
Hyperphosphorylated Tau Protein ◽  
Common Causes ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can provide temporary help with the memory symptoms and other cognitive changes of patients, however, they are not able to stop or reverse the progression of AD. New medication discovery and the development of a cure for AD is urgently in need. In this review, we summarized drugs for AD treatments and their recent updates, and discussed the potential of microglia induced neuroinflammation as a target for anti-AD drug development.

Interplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer’s Disease

2018 ◽  
Vol 15 (10) ◽  
pp. 938-950 ◽  
Author(s):  
Martina Zverova ◽  
Eva Kitzlerova ◽  
Zdenek Fisar ◽  
Roman Jirak ◽  
Jana Hroudova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Apoe Genotype ◽  
Plasma Biomarkers ◽  
Plasma Melatonin ◽  
Apoe Ε4 ◽  
Ε4 Allele ◽  
Severity Of Dementia

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD. Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease

2019 ◽  
Vol 16 (5) ◽  
pp. 418-452 ◽  
Author(s):  
Lídia Pinheiro ◽  
Célia Faustino
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Senile Plaques ◽  
Symptomatic Relief ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
App Processing

Alzheimer’s disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

Phosphorylation and Glycosylation of Amyloid-β Protein Precursor: The Relationship to Trafficking and Cleavage in Alzheimer’s Disease

2021 ◽  
pp. 1-21
Author(s):  
Xi-Jun Song ◽  
He-Yan Zhou ◽  
Yu-Ying Sun ◽  
Han-Chang Huang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Cleavage Enzyme ◽  
The Central Nervous System

Alzheimer’s disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-β (Aβ) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-β protein precursor (AβPP) through the successive cleaving by β-site AβPP-cleavage enzyme 1 (BACE1) and γ-secretase. AβPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AβPP. In the recent years, about 10 phosphorylation sites of AβPP were identified, and they play complex roles in glycosylation modification and cleavage of AβPP. In this article, we introduced the transport and the cleavage pathways of AβPP, then summarized the phosphorylation and glycosylation sites of AβPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AβPP trafficking and cleavage in order to provide theoretical basis for AD research.

scholarly journals Cerebrospinal fluid-induced retardation of amyloid β aggregation correlates with Alzheimer's disease and the APOE ε4 allele

2016 ◽  
Vol 1651 ◽  
pp. 11-16 ◽  
Author(s):  
E.R. Padayachee ◽  
H. Zetterberg ◽  
E. Portelius ◽  
J. Borén ◽  
J.L. Molinuevo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Ε4 Allele

scholarly journals Tau protein and its role in Alzheimer’s disease physiopathology: a literature review

2021 ◽  
Author(s):  
Larissa Rosa Stork ◽  
Lucca Stephani Ribeiro ◽  
Izabella Savergnini Deprá ◽  
Luísa D’Ávila Camargo ◽  
Maria Angélica Santos Novaes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Paired Helical Filaments ◽  
Tau Proteins ◽  
Molecular Aspects ◽  
Cellular Cytoskeleton

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a double proteinopathy: deposition of amyloid-β into plaques and hyperphosphorylation of Tau protein. Objectives: To understand the genetic and molecular aspects of Tau protein and its relationship with Alzheimer’s disease. Methods: We conducted a systematic literature search using Pubmed/ MEDLINE and ClinicalKey databases, applying the descriptors: “Alzheimer Disease” AND “Tau proteins’’ AND Tauopathies, during July and August of 2020. The inclusion criteria were English and Portuguese articles published between 2015 and 2020, with human limited study and free full text, excluding images, books, clinical tests, and narrative reviews. After analyzing titles and abstracts, we selected 12 articles and included 7 additional studies. Results: Mapt, the encoder gene of Tau, is located in the 17q21.3 locus and presents 16 exons that, when transcripted, originates 12 copies of mRNA by alternative splicing and 6 Tau’s isoforms. Tau is a microtubule-associated protein (MAP) responsible for cellular cytoskeleton stabilization and maintenance, promoting neuronal axonal transport. A kinase-phosphatase imbalance turns Tau hyperphosphorylated, disassociating it from tubulin and grouping it into insoluble paired helical filaments, which originates neurofibrillary tangles. The tauopathy’s progress causes neurotransmitter destabilization and neuronal death, inducing AD symptomatic manifestations. Conclusions: Due to the gradual worsening of the disease to more debilitating stages, studies focused on deepening the knowledge of genetic and molecular aspects of Tau protein are viable and promising alternatives to improve the quality of patient’s lives.

scholarly journals Alzheimer’s disease as an inflammatory disease

2017 ◽  
Vol 8 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Marta Bolós ◽  
Juan Ramón Perea ◽  
Jesús Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Short Review ◽  
Hyperphosphorylated Tau ◽  
Progressive Dementia ◽  
Hyperphosphorylated Tau Protein

AbstractAlzheimer’s disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leading to progressive dementia. In this short review, we focus on neuroinflammation in AD. Specifically, we describe the participation of microglia, as well as other factors that may contribute to inflammation, in neurodegeneration.

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