Immunotherapeutics for AD: A Work in Progress

2021 ◽  
Vol 20 ◽  
Author(s):  
Anuja Sharma ◽  
Jaspreet Singh Anand ◽  
Yatender Kumar
Keyword(s):  
Tau Protein ◽  
Therapeutic Strategy ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Genetic Defects ◽  
Multiple Factors ◽  
Neurodegenerative Process ◽  
Epigenetic Regulations

: Alzheimer's Disease (AD), often called the 'Plague of the 21st Century,' is a progressive, irreversible neurodegenerative disorder that leads to the degeneration and death of neurons. Multiple factors, such as genetic defects, epigenetic regulations, environmental factors, or cerebrovascular damage, are a manifestation of the neurodegenerative process that begins to occur decades before the onset of disease. To date, no treatment or therapeutic strategy has proven to be potent in inhibiting its progress or reversing the effects of the disease. The ever-increasing numbers and lack of sufficient therapies that can control or reverse the effects of the disease have propelled research in the direction of devising efficient therapeutic strategies for AD. This review comprehensively discusses the active and passive immunotherapies against Amyloid-β and Tau protein, which remain the popular choice of targets for AD therapeutics. Some of the prospective immunotherapies against Aβ plaques have failed due to various reasons. Much of the research is focused on targeting Tau, specifically, targeting the mid-region of extracellular Tau due to their potential to prevent seeding and hence the spread of neurofibrillary tangles (NFTs). Thus, there is a need to thoroughly understand the disease onset mechanisms and discover effective therapeutic strategies.

Aging and Neuroinflammatory Disorders: New Biomarkers and Therapeutic Targets

2019 ◽  
Vol 25 (39) ◽  
pp. 4168-4174 ◽  
Author(s):  
Caterina M. Gambino ◽  
Bruna Lo Sasso ◽  
Giulia Bivona ◽  
Luisa Agnello ◽  
Marcello Ciaccio
Keyword(s):  
Neurodegenerative Disorder ◽  
Strong Association ◽  
Disease Onset ◽  
Therapeutic Targets ◽  
Low Grade ◽  
Ongoing Research ◽  
Neurodegenerative Process ◽  
Chronic Neuroinflammation ◽  
Inflammatory Processes ◽  
New Biomarkers

: Chronic neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative age-associated disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson’s disease, and dementia. : In particular, persistent low-grade inflammation may disrupt the brain endothelial barrier and cause a significant increase of pro-inflammatory cytokines and immune cells into the cerebral tissue that, in turn, leads to microglia dysfunction and loss of neuroprotective properties. : Nowadays, growing evidence highlights a strong association between persistent peripheral inflammation, as well as metabolic alterations, and neurodegenerative disorder susceptibility. The identification of common pathways involved in the development of these diseases, which modulate the signalling and immune response, is an important goal of ongoing research. : The aim of this review is to elucidate which inflammation-related molecules are robustly associated with the risk of neurodegenerative diseases. Of note, peripheral biomarkers may represent direct measures of pathophysiologic processes common of aging and neuroinflammatory processes. In addition, molecular changes associated with the neurodegenerative process might be present many decades before the disease onset. Therefore, the identification of a comprehensive markers panel, closely related to neuroinflammation, could be helpful for the early diagnosis, and the identification of therapeutic targets to counteract the underlying chronic inflammatory processes.

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.

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 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 Imaging Techniques in Alzheimer’s Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

2021 ◽  
Vol 22 (4) ◽  
pp. 2110
Author(s):  
Wieke M. van Oostveen ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Disease Progression ◽  
Neurodegenerative Disorder ◽  
Imaging Techniques ◽  
Disease Onset ◽  
Amyloid Β ◽  
Multiple Imaging ◽  
Novel Biomarkers

Background. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting many individuals worldwide with no effective treatment to date. AD is characterized by the formation of senile plaques and neurofibrillary tangles, followed by neurodegeneration, which leads to cognitive decline and eventually death. Introduction. In AD, pathological changes occur many years before disease onset. Since disease-modifying therapies may be the most beneficial in the early stages of AD, biomarkers for the early diagnosis and longitudinal monitoring of disease progression are essential. Multiple imaging techniques with associated biomarkers are used to identify and monitor AD. Aim. In this review, we discuss the contemporary early diagnosis and longitudinal monitoring of AD with imaging techniques regarding their diagnostic utility, benefits and limitations. Additionally, novel techniques, applications and biomarkers for AD research are assessed. Findings. Reduced hippocampal volume is a biomarker for neurodegeneration, but atrophy is not an AD-specific measure. Hypometabolism in temporoparietal regions is seen as a biomarker for AD. However, glucose uptake reflects astrocyte function rather than neuronal function. Amyloid-β (Aβ) is the earliest hallmark of AD and can be measured with positron emission tomography (PET), but Aβ accumulation stagnates as disease progresses. Therefore, Aβ may not be a suitable biomarker for monitoring disease progression. The measurement of tau accumulation with PET radiotracers exhibited promising results in both early diagnosis and longitudinal monitoring, but large-scale validation of these radiotracers is required. The implementation of new processing techniques, applications of other imaging techniques and novel biomarkers can contribute to understanding AD and finding a cure. Conclusions. Several biomarkers are proposed for the early diagnosis and longitudinal monitoring of AD with imaging techniques, but all these biomarkers have their limitations regarding specificity, reliability and sensitivity. Future perspectives. Future research should focus on expanding the employment of imaging techniques and identifying novel biomarkers that reflect AD pathology in the earliest stages.

scholarly journals p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function

2022 ◽  
Author(s):  
Juan R. Perea ◽  
Marta Bolós ◽  
Raquel Cuadros ◽  
Esther García ◽  
Vega García-Escudero ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Primary Microglia ◽  
Chronic Inflammatory Response ◽  
The Past ◽  
The Central Nervous System ◽  
Tau Aggregation

AbstractAlzheimer’s disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.

Tau in Alzheimer's Disease: Mechanisms and Therapeutic Strategies

2018 ◽  
Vol 15 (3) ◽  
pp. 283-300 ◽  
Author(s):  
Yu Gao ◽  
Lin Tan ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Therapeutic Strategy ◽  
Recent Literature ◽  
Neurodegenerative Disorder ◽  
Therapeutic Strategies ◽  
Behavioral Disabilities ◽  
Disease Mechanisms ◽  
Immunization Strategies

Objective: Alzheimer's disease (AD), the most important progressive neurodegenerative disorder, is characterized by cognitive and behavioral disabilities. Nowadays, tau, as a microtubuleassociated protein and a principle neuropathological hallmark of AD, provides us a neoteric perspective to explore further aetiopathogenesis and therapeutic strategy. The hyperphosphorylation and abnormal aggregation of tau, combined with its decreased clearance, form neurofibrillary tangles (NFTs) and exert neurotoxicity in AD. Methods: Recent investigations aim to prevent the deposition of NFT and accelerate the clearance of NFT. Intriguingly, immunization strategies targeting tau effectively ameliorates the tau-associated pathology in AD. In addition, modified therapies targeting tau should be regarded as a potential way to treat AD. These progresses open new avenues for AD. Conclusion: Here, we review the recent literature of potential mechanisms of the tau in AD and discuss the modified therapeutic strategies for AD.

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 Dietary Vitamin B12 reduces amyloid-β proteotoxicity by alleviating oxidative stress and mitochondrial dysfunction

2021 ◽  
Author(s):  
Andy B. Lam ◽  
Kirsten Kervin ◽  
Jessica E. Tanis
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Amyloid Β ◽  
Dietary Vitamin ◽  
Antioxidant Vitamin ◽  
Vitamin B ◽  
The Impact ◽  
And Oxidative Stress

SUMMARYAlzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis including amyloid beta (Aβ) deposition, mitochondrial dysfunction, and oxidative stress. Here we used Caenorhabditis elegans to define the impact of diet on Aβ proteotoxicity. We discovered that dietary vitamin B12 alleviated mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying Aβ-induced paralysis without affecting Aβ accumulation. Vitamin B12 had this protective effect by acting as a cofactor for methionine synthase rather than as an antioxidant. Vitamin supplementation of B12 deficient adult Aβ animals was beneficial, demonstrating potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by both aging and proteotoxic stress.

Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

2019 ◽  
Vol 26 (20) ◽  
pp. 3719-3753 ◽  
Author(s):  
Natasa Kustrimovic ◽  
Franca Marino ◽  
Marco Cosentino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Neurodegenerative Process ◽  
Progressive Degeneration ◽  
Cytokine Levels ◽  
Inflammatory Phenotype ◽  
Immune Challenges

:Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.:In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

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