scholarly journals The Essentials of Biochemistry of the Proteins as Related to Alzheimer’s Disease: A Review

2020 ◽  
pp. 34-49
Author(s):  
A. S. V. Prasad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Therapeutic Strategies ◽  
Intracellular Domain ◽  
Amyloid Beta Precursor Protein ◽  
Terminal Fragment ◽  
Alois Alzheimer ◽  
Tau Kinases ◽  
Amyloid Cascade

Amyloid plaques and Tau tangles, constitute the pathological hallmarks of the brains of the patients suffering from Alzheimer’s disease. They are identified as far back as 1996 by Alois Alzheimer, a German psychiatrist and neuropathologist, but till this date, how they produce neuronal death remained an enigma. The amyloid cascade theory held its sway until recent times until the emphasis is shifted to the metabolites of amyloid Beta precursor protein (APP). Several metabolites of APP are formed depending on by which pathway, the APP is metabolized, either by the non -amyloidogenic pathway (forming α-C terminal fragment -CTFα / C83 and the N-terminal fragment sAPPα / P3 and the APP intracellular domain AICD). Or amyloidogenic pathways. (Forming extracellular Aβ and APP intracellular domain -AICD). The hyperphosphorylation is held responsible for the tau protein tangles. The over activity of the tau kinases or the failure of inhibition by the tau phosphatases is implicated, in tau tangle deposits. These biochemical aspects of AD assumed importance in connection with the interventional therapeutic strategies that are developed in the years bygone, as well as those still are in the developing stage. In keeping with this fact, it is attempted to review the essentials of the biochemical aspects of the involved proteins, as related to AD, in this article.

scholarly journals Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Tomasz Jaworski ◽  
Sebastian Kügler ◽  
Fred Van Leuven
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Amyloid Plaques ◽  
Amyloid Peptides ◽  
Alois Alzheimer ◽  
Second Shift ◽  
Amyloid Cascade

Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the “concrete” deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions.

scholarly journals The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Daniel A. Bórquez ◽  
Christian González-Billault
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Intracellular Domain ◽  
Multiprotein Complexes ◽  
Amyloid Cascade

Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation ofβ-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβfragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD.

scholarly journals Alzheimer’s disease: a molecular mechanism, new hypotheses, and therapeutic strategies

Medicina ◽  
2010 ◽  
Vol 46 (1) ◽  
pp. 70 ◽  
Author(s):  
Milda Plečkaitytė
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Developed Countries ◽  
Therapeutic Strategies ◽  
Self Assembling ◽  
Parkinson’S Diseases ◽  
Cellular Pathogenesis ◽  
The Developed Countries ◽  
Amyloid Cascade

Human diseases involving protein misfolding and aggregation have received increasing attention in recent years. Alzheimer’s disease and other diseases associated with aging are sweeping the developed countries whose populations are rapidly aging. Recent progress has improved our knowledge about molecular and cellular pathogenesis of these diseases. For more than 20 years, multiple diseases such as Alzheimer’s and Parkinson’s diseases have been associated with accumulation of abnormal protein fibrils. These self-assembling fibrils, referred as “amyloid,” have been considered the pathogenic molecules that cause cellular degeneration. Accumulation of fibrillar Aβ in plaques underlies the theory for Alzheimer’s disease. Recent experiments have provided evidence that fibrils are not the only neurotoxins. Soluble oligomers and protofibrils play a crucial role in causing cellular dysfunction and death. These oligomers, the missing links in the original amyloid cascade hypothesis, have been incorporated into an updated amyloid cascade. Despite new information gained, there is no disease-modifying treatment. New insights into disease mechanisms and new therapeutic strategies give hope for change.

THE EU/US TASK FORCE’S FUTURE FOR ANTI-AMYLOID TRIALS: FAITES VOS JEUX

2020 ◽  
pp. 1-2
Author(s):  
L.S. Schneider
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phenotypic Expression ◽  
Amyloid Plaques ◽  
Scientific Investigation ◽  
Amyloid Cascade Hypothesis ◽  
Amyloid Cascade ◽  
The Eu

To be clear, the amyloid cascade hypothesis is well-established, beyond dispute, and ‘alive and well’ as a framework for the scientific investigation of Alzheimer’s disease. Imbalances in amyloid production and clearance occur very early and are seminal factors in the pathophysiology and phenotypic expression of the illness (1, 2). Although we define clinical Alzheimer’s by amyloid plaques, consider aggregates as initiating events, and note that several amyloid-related genotypes are causative or protective, this does not mean that targeting any component of the amyloid cascade necessarily will be therapeutic. Other factors may be at play.

Insulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses

2021 ◽  
pp. 1-35
Author(s):  
Suélen Santos Alves ◽  
Rui Milton Patrício da Silva-Junior ◽  
Gabriel Servilha-Menezes ◽  
Jan Homolak ◽  
Melita Šalković-Petrišić ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Experimental Models ◽  
Current Medical ◽  
Amyloid Cascade Hypothesis ◽  
Alois Alzheimer ◽  
First Time ◽  
Amyloid Cascade

Almost 115 years ago, Alois Alzheimer described Alzheimer’s disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.

scholarly journals New therapeutic strategies for Alzheimer’s disease

2021 ◽  
Vol 75 ◽  
pp. 474-490
Author(s):  
Dominika Nowak ◽  
Wojciech Słupski ◽  
Maria Rutkowska
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Tau Protein ◽  
Amyloid Β ◽  
Current Treatment ◽  
Therapeutic Strategies ◽  
Hyperphosphorylated Tau Protein ◽  
Glutamatergic Signaling ◽  
Amyloid Cascade

Alzheimer’s disease (AD) described as a chronic and irreversible neurodegenerative disease remains the most common cause of dementia. Due to the aging of the population, the incurability of AD has become a growing problem of medicine in the 21stcentury. Current treatment is only symptomatic, providing minimal, temporary improvement in the patient’s cognitive function. This paper presents the latest trends in the search for effective pharmacotherapy capable of preventing or inhibiting AD progression. Since the exact pathogenesis of Alzheimer’s disease is not known, the main therapeutic strategies are based only on the following hypotheses: amyloid cascade, tau protein, oxidative stress, neuroinflammation and those associated with dysfunction of the cholinergic system as well as glutamatergic. Most of the compounds currently tested in clinical trials are targeted at pathological amyloid β (A β), which is considered the cause of neurodegeneration, according to the most widely described cascade theory. Most of the compounds currently tested in clinical trials are targeted at pathological amyloid β (Aβ), which is the main cause of neurodegeneration according to the widely described theory of the amyloid cascade. Attempts to fight the toxic Aβ are based on the following: immunotherapy (vaccines, monoclonal antibodies), compounds that inhibit its formation: γ-secretase inhibitors/modulators and β-secretase. Immunotherapy can also be us,ed to increase the clearance of hyperphosphorylated tau protein, the occurrence of which is another feature of Alzheimer’s disease. In addition to immunotherapy, anti-inflammatory, metabolic and neuroprotective compounds have been the subject of a number of studies. A range of symptomatic compounds that improve cognitive functions by compensating cholinergic, noradrenergic and glutamatergic signaling deficits have also been investigated in clinical trials.

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.

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