scholarly journals Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer’s Disease

2020 ◽  
Vol 13 ◽  
Author(s):  
Bhanu Chandra Karisetty ◽  
Akanksha Bhatnagar ◽  
Ellen M. Armour ◽  
Mariah Beaver ◽  
Haolin Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Synaptic Function ◽  
Gene Control ◽  
Amyloid Β Peptide

scholarly journals Exploring Aβ Proteotoxicity and Therapeutic Candidates Using Drosophila melanogaster

2021 ◽  
Vol 22 (19) ◽  
pp. 10448
Author(s):  
Greta Elovsson ◽  
Liza Bergkvist ◽  
Ann-Christin Brorsson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Model Organism ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Disease Genes ◽  
Amyloid Β Peptide ◽  
Drug Candidates ◽  
Human Disease Genes

Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is able to uncover anti-proteotoxic candidates due to its outstanding genetic toolbox and resemblance to human disease genes. In this review, we highlight the use of Drosophila melanogaster to both study the proteotoxicity of the amyloid-β peptide and to screen for drug candidates. Expanding the knowledge of how the etiology of Alzheimer’s disease is related to proteotoxicity and how drugs can be used to block disease progression will hopefully shed further light on the field in the search for disease-modifying treatments.

scholarly journals MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities

2021 ◽  
Vol 13 ◽  
Author(s):  
Nermeen Z. Abuelezz ◽  
Fayza Eid Nasr ◽  
Mohammad Ahmed AbdulKader ◽  
Ahmad R. Bassiouny ◽  
Amira Zaky
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Functions ◽  
De Novo ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Sensory Function ◽  
Current Status ◽  
Amyloid Β Peptide ◽  
Pain Sensitization

Alzheimer's disease (AD) is a progressive and deleterious neurodegenerative disease, strongly affecting the cognitive functions and memory of seniors worldwide. Around 58% of the affected patients live in low and middle-income countries, with estimates of increasing deaths caused by AD in the coming decade. AD is a multifactor pathology. Mitochondrial function declines in AD brain and is currently emerging as a hallmark of this disease. It has been considered as one of the intracellular processes severely compromised in AD. Many mitochondrial parameters decline already during aging; mitochondrial efficiency for energy production, reactive oxygen species (ROS) metabolism and the de novo synthesis of pyrimidines, to reach an extensive functional failure, concomitant with the onset of neurodegenerative conditions. Besides its impact on cognitive functions, AD is characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated Tau protein, accompanied by drastic sleep disorders, sensory function alterations and pain sensitization. Unfortunately, till date, effective management of AD-related disorders and early, non-invasive AD diagnostic markers are yet to be found. MicroRNAs (miRNAs) are small non-coding nucleic acids that regulate key signaling pathway(s) in various disease conditions. About 70% of experimentally detectable miRNAs are expressed in the brain where they regulate neurite outgrowth, dendritic spine morphology, and synaptic plasticity. Increasing studies suggest that miRNAs are intimately involved in synaptic function and specific signals during memory formation. This has been the pivotal key for considering miRNAs crucial molecules to be studied in AD. MicroRNAs dysfunctions are increasingly acknowledged as a pivotal contributor in AD via deregulating genes involved in AD pathogenesis. Moreover, miRNAs have been proved to control pain sensitization processes and regulate circadian clock system that affects the sleep process. Interestingly, the differential expression of miRNA panels implies their emerging potential as diagnostic AD biomarkers. In this review, we will present an updated analysis of miRNAs role in regulating signaling processes that are involved in AD-related pathologies. We will discuss the current challenges against wider use of miRNAs and the future promising capabilities of miRNAs as diagnostic and therapeutic means for better management of AD.

scholarly journals Role of miRNAs in Alzheimer's Disease and Possible Fields of Application

2019 ◽  
Vol 20 (16) ◽  
pp. 3979 ◽  
Author(s):  
Silvestro ◽  
Bramanti ◽  
Mazzon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Senile Dementia ◽  
Amyloid Β ◽  
Synaptic Function ◽  
In Vivo Studies ◽  
Transcriptional Gene Silencing ◽  
Amyloid Β Peptide

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3’ and 5’ untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

scholarly journals A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

2021 ◽  
pp. 1-20
Author(s):  
Yang Yu ◽  
Yang Gao ◽  
Bengt Winblad ◽  
Lars Tjernberg ◽  
Sophia Schedin Weiss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Stimulated Emission ◽  
Amyloid Β Peptide ◽  
Primary Neurons ◽  
Amyloid Β Protein ◽  
Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

Conformation-Specific Perturbation of Membrane Dynamics by Structurally Distinct Oligomers of Alzheimer's Amyloid-β Peptide

2021 ◽  
Author(s):  
Priyanka Madhu ◽  
Debapriya Das ◽  
Samrat Mukhopadhyay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Membrane Dynamics ◽  
Amyloid Β Peptide

The accumulation of toxic soluble oligomers of the amyloid-β peptide (Aβ) is a key step in the pathogenesis of Alzheimer’s disease. There are mainly two conformationally distinct oligomers, namely, prefibrillar...

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