scholarly journals Differential contribution of isoaspartate post-translational modifications to the fibrillization and toxic properties of amyloid β and the Asn23 Iowa mutation

2013 ◽  
Vol 456 (3) ◽  
pp. 347-360 ◽  
Author(s):  
Silvia Fossati ◽  
Krysti Todd ◽  
Krystal Sotolongo ◽  
Jorge Ghiso ◽  
Agueda Rostagno
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Pharmacological Effect ◽  
Cell Toxicity ◽  
Post Translational Modifications ◽  
Differential Contribution ◽  
Insight Into

The present study highlights the contribution of the post-translational isoaspartate modification and the D23N mutation to the aggregation/oligomerization and cell toxicity properties of amyloid β in Alzheimer's disease, providing insight into mitochondrial engagement, the resulting apoptotic mechanisms and the protective pharmacological effect of methazolamide.

The Involvement of Post-Translational Modifications in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 313-335 ◽  
Author(s):  
Serena Marcelli ◽  
Massimo Corbo ◽  
Filomena Iannuzzi ◽  
Lucia Negri ◽  
Fabio Blandini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Modification ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Normal Function ◽  
Ageing Population ◽  
Covalent Bonds ◽  
Post Translational Modifications ◽  
Related Proteins

Background: Alzheimer's disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Methods: Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Results: Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. Conclusion: We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs.

scholarly journals Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages

2020 ◽  
Vol 9 (6) ◽  
pp. 1713 ◽  
Author(s):  
Gabriela Dumitrita Stanciu ◽  
Veronica Bild ◽  
Daniela Carmen Ababei ◽  
Razvan Nicolae Rusu ◽  
Alina Cobzaru ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Social Impact ◽  
Significant Risk ◽  
Amyloid Β ◽  
Detailed Knowledge ◽  
Amyloid Aggregation ◽  
Islet Amyloid ◽  
Type 3 ◽  
Insight Into

Diabetes and Alzheimer’s disease are two highly prevalent diseases among the aging population and have become major public health concerns in the 21st century, with a significant risk to each other. Both of these diseases are increasingly recognized to be multifactorial conditions. The terms “diabetes type 3” or “brain diabetes” have been proposed in recent years to provide a complete view of the potential common pathogenic mechanisms between these diseases. While insulin resistance or deficiency remains the salient hallmarks of diabetes, cognitive decline and non-cognitive abnormalities such as impairments in visuospatial function, attention, cognitive flexibility, and psychomotor speed are also present. Furthermore, amyloid aggregation and deposition may also be drivers for diabetes pathology. Here, we offer a brief appraisal of social impact and economic burden of these chronic diseases and provide insight into amyloidogenesis through considering recent advances of amyloid-β aggregates on diabetes pathology and islet amyloid polypeptide on Alzheimer’s disease. Exploring the detailed knowledge of molecular interaction between these two amyloidogenic proteins opens new opportunities for therapies and biomarker development.

scholarly journals Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Prasad Tammineni ◽  
Xuan Ye ◽  
Tuancheng Feng ◽  
Daniyal Aikal ◽  
Qian Cai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Retrograde Transport ◽  
Presynaptic Terminals ◽  
Aβ Oligomers ◽  
Autophagic Vacuoles ◽  
Axonal Pathology ◽  
Mechanistic Insight ◽  
Insight Into

Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer’s disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-β (Aβ) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD.

scholarly journals Tau-first subtype of Alzheimer's disease consistently identified across in vivo and post mortem studies

2020 ◽  
Author(s):  
Leon M Aksman ◽  
Neil P Oxtoby ◽  
Marzia A Scelsi ◽  
Peter A Wijeratne ◽  
Alexandra L Young ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Post Mortem ◽  
Positron Emission ◽  
Soluble Trem2 ◽  
The Brain ◽  
Insight Into

Alzheimer's disease (AD) is marked by the spread of misfolded amyloid-β and tau proteins throughout the brain. While it is commonly believed that amyloid-β abnormality drives the cascade of AD pathogenesis, several in vivo and post mortem studies indicate that in some subjects localized tau-based neurofibrillary tangles precede amyloid-β pathology. This suggests that there may be multiple distinct subtypes of protein aggregation pathways within AD, with potentially different demographic, cognitive and comorbidity profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post mortem immunohistochemistry and in vivo positron emission tomography (PET) and cerebrospinal fluid (CSF) based measures of protein pathologies in two large observational cohorts. We consistently identified both amyloid-first and tau-first AD subtypes, where tau-first subjects had higher levels of soluble TREM2 compared to amyloid-first subjects. Our work provides insight into AD progression that may be valuable for interventional trials targeting amyloid-β and tau.

scholarly journals Animal Models for Alzheimer's Disease and Frontotemporal Dementia: A Perspective

ASN NEURO ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. AN20090042 ◽  
Author(s):  
Jürgen Götz ◽  
Naeman N Götz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Frontotemporal Dementia ◽  
Amyloid Β ◽  
Human Condition ◽  
Aβ Amyloid ◽  
Dementia Research ◽  
Insight Into ◽  
Research Animal

In dementia research, animal models have become indispensable tools. They not only model aspects of the human condition, but also simulate processes that occur in humans and hence provide insight into how disease is initiated and propagated. The present review discusses two prominent human neurodegenerative disorders, Alzheimer's disease and frontotemporal dementia. It discusses what we would like to model in animals and highlights some of the more recent achievements using species as diverse as mice, fish, flies and worms. Advances in imaging and therapy are explored. We also discuss some anticipated new models and developments. These will reveal how key players in the pathogenesis of Alzheimer's disease and frontotemporal dementia, such as the peptide Aβ (amyloid β) and the protein tau, cause neuronal dysfunction and eventually, neuronal demise. Understanding these processes fully will lead to early diagnosis and therapy.

Potential roles of α-amylase in Alzheimer’s disease: Biomarker and drug target

2021 ◽  
Vol 20 ◽  
Author(s):  
Win Ning Chen ◽  
Kim San Tang ◽  
Keng Yoon Yeong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Target ◽  
Specific Activity ◽  
Amyloid Β ◽  
Vital Role ◽  
Amylase Inhibitors ◽  
Insight Into

: Alzheimer’s disease (AD), the most common form of dementia, is pathologically characterized by the deposition of amyloid-β plaques and the formation of neurofibrillary tangles. In a neurodegenerative brain, glucose metabolism is also impaired and considered as one of the key features in AD patients. The impairment causes a reduction in glucose transporters and the uptake of glucose as well as alterations in the specific activity of glycolytic enzymes. Recently, it has been reported that α-amylase, a polysaccharide-degrading enzyme, is present in the human brain. The enzyme is known to be associated with various diseases such as type 2 diabetes mellitus and hyperamylasaemia. With this information at hand, we hypothesize that α-amylase could have a vital role in the demented brains of AD patients. This review aims to shed insight into the possible link between the expression levels of α-amylase and AD. Lastly, we also cover the diverse role of amylase inhibitors and how they could serve as a therapeutic agent to manage or stop AD progression.

scholarly journals Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

2019 ◽  
Vol 10 (44) ◽  
pp. 10343-10350 ◽  
Author(s):  
Zhi Du ◽  
Dongqin Yu ◽  
Xiubo Du ◽  
Peter Scott ◽  
Jinsong Ren ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Click Reaction ◽  
Cycloaddition Reaction ◽  
Amyloid Β ◽  
Drug Synthesis ◽  
Insight Into

Accumulated Cu in amyloid-β plaques can effectively catalyze the azide–alkyne cycloaddition reaction for fluorophore activation and drug synthesis. Our work may provide new insight intoin situdrug synthesis for neurodegenerative diseases.

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