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.

scholarly journals Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Jaume Folch ◽  
Dmitry Petrov ◽  
Miren Ettcheto ◽  
Sonia Abad ◽  
Elena Sánchez-López ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metabotropic Glutamate Receptor ◽  
Developed Countries ◽  
Metabotropic Glutamate ◽  
Amyloid A ◽  
Slowing Down ◽  
Fyn Kinase ◽  
Nmdar Activation ◽  
The Developed Countries

Alzheimer’s disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβproduction through the inhibition ofβandγsecretase enzymes and (b) to promote dissolution of existing cerebral Aβplaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβsignalling, particularly at the synapse. Aβoligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβis bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

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.

Alzheimer’s Disease: Special Focus on the Efficacy of Computer-Based Training Programs - A Mini-Review

2018 ◽  
Vol 15 (13) ◽  
pp. 1213-1219 ◽  
Author(s):  
Blanka Klimova ◽  
Kamil Kuca ◽  
Petra Maresova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Information Technologies ◽  
Training Programs ◽  
Developed Countries ◽  
Special Focus ◽  
Computer Based Training ◽  
Computer Based ◽  
The Developed Countries

Background: At present, the number of older people is growing, especially in the developed countries where the living conditions enable a longer life expectancy. However, the higher age may result in the aging diseases such as dementia out which Alzheimer’s disease (AD) is the most frequent. Nevertheless, to maintain them both physically and mentally active, more assistance is required. Objective: The purpose of this study is to discuss the efficacy of the use of modern information technologies, especially computer-based training programs, on people with Alzheimer’s disease (AD). Results: Although the results from the selected studies do not indicate that the computer-based training programs are effective in the delay of cognitive decline is concerned, they suggest that these computerbased training programs are at least appropriate for the improvement of their behavioural symptoms and progression of the disease. Conclusion: Generally, these technological devices may contribute to the reduction of patients´ and their caregivers´ costs and certain flexibility, and thus the improvement of the quality of their life.

Missing Uniform Costs Classification for Alzheimer’s Disease Treatment and Care

2018 ◽  
Vol 15 (14) ◽  
pp. 1297-1303 ◽  
Author(s):  
Petra Maresova ◽  
Kamil Kuca
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
National Level ◽  
Indirect Costs ◽  
Developed Countries ◽  
Direct Costs ◽  
Community Health Services ◽  
The European Union ◽  
People With Dementia ◽  
The Developed Countries

Background: The importance of the issue of the economic burden of treatment and care for people with dementia is crucial in the developed countries. The European Union and other developed countries are trying to improve the course of aging population which leads to rising costs. Their uniform registration is also one of the objectives of the developed countries’ strategic plans to fight dementia. The individual steps of the plans in practical terms so far are mainly directed to the early diagnosis of diseases, records of the associated data are so far in the background. Aim: The aim of this paper is to specify a set of costs that should be constantly monitored at the national level within dementia. Methods: The main method is a literature review focused on Alzheimer's disease. The searched keywords were "Alzheimer's disease" and "costs" incurred after 2010. The studies will specify the monitored costs and determine their minimal penetration, which will then form the basis for recommendations for the monitored group of costs on a national level. Results: Results of the analysis indicate that the following main cost groups are monitored: medical direct costs (inpatient care, outpatient treatment, medication), non-medical direct costs (day care centres, community health services, respite care, accommodation costs for patients) and indirect costs (time that the carers dedicate to the patient). The issue of different naming and groups of costs calls for a common strategy in this area and defining the minimum items that should be monitored.

Current theories for the molecular and cellular pathogenesis of Alzheimer's disease

2001 ◽  
Vol 3 (16) ◽  
pp. 1-11 ◽  
Author(s):  
Gunnar K. Gouras
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Process ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Cellular Pathogenesis ◽  
Amyloid Cascade ◽  
The Brain ◽  
Aβ Production ◽  
Prevailing View

Over the past decade, the prevailing view for the molecular and cellular pathogenesis of Alzheimer's disease (AD) has centred on the β-amyloid (Aβ) peptide that accumulates in vulnerable brain areas in the disease. The amyloid cascade hypothesis postulates that the build up of Aβ in the brain causes damage to neurons, leading to dysfunction and loss of neurons, and the clinical phenotype of the amnestic dementia characteristic of AD. All known mutations that result in autosomal dominant forms of early-onset familial AD cause increased production of Aβ42, a form of Aβ that is particularly relevant in AD. Other proteins that are crucial to the pathogenesis of AD are the presenilins 1 and 2, which are intimately involved with Aβ production and when mutated in familial forms of AD cause increases in Aβ42. Currently, challenges in AD research include determining the earliest pathological effects of Aβ42, how the important AD risk factor apolipoprotein E affects the disease process, whether presenilin is the elusive γ-secretase, and how levels of Aβ can be effectively reduced therapeutically.

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.

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.

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.

Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

2020 ◽  
Vol 20 (26) ◽  
pp. 2380-2390 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Abdullah Al Mamun ◽  
Md. Ataur Rahman ◽  
Tapan Behl ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Cell Organelles ◽  
The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

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