scholarly journals Monoclonal antibodies in the treatment of Alzheimer’s disease: a literature review

2021 ◽  
Author(s):  
Pedro Henrique Carvalho Furtado de Mendonça ◽  
Fernanda Rabello Detoni ◽  
Letícia Silva Brandão dos Santos ◽  
Talita Cardoso Gomes ◽  
Ivan Magalhães Viana
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoclonal Antibodies ◽  
Neurodegenerative Disorder ◽  
Controlled Trial ◽  
Test Group ◽  
Pubmed Database ◽  
Significant Difference ◽  
Collateral Effects ◽  
Aβ Aggregation

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder, whose treatment is limited to drugs that offer comfort to the patient. Immunotherapy with monoclonal antibodies (mAbs) has been the subject of a study with the promise of reversing cognitive deficits. In this scenario, we conducted a systematic review to elucidate aspects about the effectiveness of such treatment. Objectives: Analyze the prognostic of patients with AD through immunotherapy using anti-amilody mAbs. Methods: It was used the PubMed database using the descriptors: “Amyloid beta-Peptides AND Alzheimer disease AND Immunotherapy”. Filters: clinical trial, randomized controlled trial. 6 articles from 2015 to 2021 were selected. Inclusion criteria: (1) mAbs as treatment for AD; (2) Analyze the prognostic. Results: The immunotherapy with bapineuzumab and solanezumab didn’t showed no statistically significant difference between the groups of bapineuzumab 0,5 mg / kg (p = 0,979) and placebo (p = 0,973) and a change of 6.65 in the solanezumab group and 7.44 in the placebo group (difference, −0.80; P = 0 , 10). However, subcutaneous treatment of bapineuzumab exhibited fewer abnormalities of images related to amyloid with edema or effusion (AIRA), so, better tolerated compared to intravenous treatment. In the study with the ABvac40 vaccine, about 92% of the individuals in the test group developed specific anti-Aβ 40 antibodies. Conclusion: Bapineuzumab and solanezumab didn’t achieve significant results in the reduction of cognitive decline, however bapineuzumab enabled the prevention of Aβ aggregation. However, the use of mAbs can trigger collateral effects, requiring an individual analysis.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

2019 ◽  
Vol 90 (7) ◽  
pp. 740-746 ◽  
Author(s):  
Martha S Foiani ◽  
Claudia Cicognola ◽  
Natalia Ermann ◽  
Ione O C Woollacott ◽  
Carolin Heller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Frontotemporal Dementia ◽  
Neurodegenerative Disorder ◽  
The Novel ◽  
Tau Pathology ◽  
Total Tau ◽  
Significant Difference ◽  
T Tau

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

scholarly journals Investigation of five polymorphic DNA markers associated with late onset Alzheimer disease

Genetika ◽  
2013 ◽  
Vol 45 (2) ◽  
pp. 503-514 ◽  
Author(s):  
Jalal Gharesouran ◽  
Maryam Rezazadeh ◽  
Mohaddes Mojtaba
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Markers ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
The Elderly ◽  
Healthy Controls ◽  
Genotype Frequencies ◽  
Significant Difference ◽  
And Control

Alzheimer's disease is a complex neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. The aim of our study was to examine the polymorphic DNA markers CCR2 (+190 G/A), CCR5?32, TNF-? (-308 G/A), TNF-? (-863 C/A) and CALHM1 (+394 C/T) to determine the relationship between these polymorphisms and the risk of late onset Alzheimer's disease in the population of Eastern Azerbaijan of Iran. A total of 160 patient samples and 163 healthy controls were genotyped by PCR-RFLP and the results confirmed using bidirectional sequencing. Statistical analysis of obtained data revealed non-significant difference between frequency of CCR5?32 in case and control groups. The same result was observed for TNF-? (-863 C/A) genotype and allele frequencies. Contrary to above results, significant differences were detected in frequency of TNF-? (-308 G/A) and CCR2-64I genotypes between the cases and healthy controls. A weak significant difference observed between allele and genotype frequencies of rs2986017 in CALHM1 (+394 C/T; P86L) in patient and control samples. It can be concluded that the T allele of P86L variant in CALHM1 & +190 G/A allele of CCR2 have a protective role against abnormal clinical features of Alzheimer's disease.

scholarly journals Monoclonal antibodies: a new trend for the treatment of Alzheimer’s disease?

2021 ◽  
Author(s):  
Letícia Escorse Requião ◽  
Giulia Freitas ◽  
Mayanna Macedo ◽  
Hanny Gondim ◽  
Blenda Antunes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Amyloid Peptide ◽  
Phase Iii ◽  
Functional Improvement ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Pubmed Database

Introduction: Alzheimer’s disease (AD) is the main form of senile dementia. Most of the supposedly disease-modifying treatments in development are directed against the β-amyloid peptide, the administration of exogenous anti-Aβ monoclonal antibodies is a passive immunization strategy aimed at resolving the aggregation of this substance. Objective: Analyze the effectiveness of monoclonal antibodies in the treatment of Alzheimer’s disease. Methods: This is a literature review, based on randomized clinical trials published between 2014 and 2021. The search was conducted in the PubMed database. Results: According to the eligibility criteria, 10 articles were selected. Two of the randomized, double-blind, placebo-controlled phase III studies, one published in 2018 and the other published in 2016, evaluated the intervention with Solanezumab and Bapineuzumab, respectively. Both were not shown to be statistically significant (P = 0.10) for the outcome improvement of the score in the cognitive subscale of 14 and 11 items “Alzheimer’s Disease Assessment Scale” (ADAS-cog14 / 11). However, in a phase II randomized placebo-controlled clinical trial, published in 2021, the use of Donanemab in patients with early Alzheimer’s disease resulted in statistically significant cognitive and functional improvement (P = 0.04) for the outcome change in the scale “Integrated Alzheimer’s Disease Rating” (iADR). Conclusion: Although the use of Donanemab has resulted in cognitive and functional improvement, randomized, double-blind, placebo-controlled, phase III clinical trials need to be conducted to prove the efficacy and safety of its use in clinical practice. Other monoclonal antibodies evaluated did not demonstrate evidence of benefit.

scholarly journals Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6015
Author(s):  
Beatrice Bargagna ◽  
Lidia Ciccone ◽  
Susanna Nencetti ◽  
M. Amélia Santos ◽  
Sílvia Chaves ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ferulic Acid ◽  
Neurodegenerative Disorder ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Biological Evaluation ◽  
Oral Drugs ◽  
Pharmacokinetic Properties ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.

scholarly journals Comparison of Early Interventions in the Prevention of Alzheimer’s Disease in Patients with Down Syndrome: A Systematic Review

2021 ◽  
Author(s):  
Yago Ricardo Pedrosa ◽  
Jossielly Rodrigues Pinheiro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Controlled Trial ◽  
Early Interventions ◽  
Significant Difference ◽  
Group A ◽  
The Subject ◽  
Group B ◽  
Almost All

Background: Down Syndrome (DS) is the most common chromosomal abnormality with an incidence of 1:700 live births. Alzheimer’s disease (AD) affects almost all of these individuals from the age of 30, whose susceptibility is on the rise with increasing life expectancy. However, interventions can limit or improve cognitive decline. Objectives: To compare early interventions in the prevention of AD in patients with DS. Methods: Randomized Controlled Trial published in English, in the last 5 years, in humans, at PUBMED. Were included studies involving participants over 18 years old, diagnosed with DS and those with unclear interventions were excluded. Six articles were found and after applying the criteria, two studies were part of this review. The PRISMA scale was used. Results: Ptomey et al. (2018) intervened with online exercise, selecting 27 participants divided into two groups: A) one session/week; B) two sessions/ week. After 12 weeks it was observed that group B showed improvement in learning compared to group A. Sano et al. (2016) performed an intervention with Vitamin E (VE) for three years in 337 individuals, segregated in: A) 1,000 IU, orally, twice/day; B) placebo. There was no significant difference in the progression of cognitive, functional, behavioral and clinical deterioration between the groups. Conclusions: The practice of physical exercise proved to be promising in the prevention of AD, however the use of VE did not show significant results. Further studies on the subject are needed.

scholarly journals Association of MS4A6A, CD33, and TREM2 gene polymorphisms with the late-onset Alzheimer’s disease

Bioimpacts ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 219-225 ◽  
Author(s):  
Elham Mehdizadeh ◽  
Mohammad Khalaj-Kondori ◽  
Zeinab Shaghaghi-Tarakdari ◽  
Saeed Sadigh-Eteghad ◽  
Mahnaz Talebi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Polymorphisms ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Salting Out ◽  
Age And Gender ◽  
Blood Samples ◽  
Significant Difference ◽  
And Gender

Introduction: Alzheimer’s disease (AD), which is a progressive neurodegenerative disorder, causes structural and functional brain disruption. MS4A6A, TREM2, and CD33 gene polymorphisms loci have been found to be associated with the pathobiology of late-onset AD (LOAD). In the present study, we tested the hypothesis of association of LOAD with rs983392, rs75932628, and rs3865444 polymorphisms in MS4A6A, TREM2, CD33 genes, respectively.Methods: In the present study, 113 LOAD patients and 100 healthy unrelated age- and gender-matched controls were selected. DNA was extracted from blood samples by the salting-out method and the genotyping was performed by RFLP-PCR. Electrophoresis was carried out on agarose gel. Sequencing was thereafter utilized for the confirmation of the results. Results: Only CD33 rs3865444 polymorphism revealed a significant difference in the genotypic frequencies of GG (P = 0.001) and GT (P = 0.001), and allelic frequencies of G (P = 0.033) and T (P = 0.03) between LOAD patients and controls. Conclusion: The evidence from the present study suggests that T allele of CD33 rs3865444 polymorphism is associated with LOAD in the studied Iranian population.

scholarly journals Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-target Agents for the Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3100 ◽  
Author(s):  
Xiao-Qin Wang ◽  
Chu-Ping Zhao ◽  
Long-Cheng Zhong ◽  
De-Ling Zhu ◽  
De-Hao Mai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Aged People ◽  
Structure Activity ◽  
Aβ Aggregation ◽  
Aggregation Inhibition ◽  
Low Toxicity ◽  
Multifunctional Agents

Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ1–42 aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a N,N-dimethylaminoalkylamino moiety at the 4-position increased the Aβ1–42 aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound 6b1, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu2+-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ1–42 aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound 6b1 showed low toxicity and a good neuroprotective effect against Aβ1–42-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound 6b1 significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound 6b1 was a promising multi-target compound worthy of further study for AD.

Donepezil Derivatives Targeting Amyloid-β Cascade in Alzheimer's Disease

2019 ◽  
Vol 16 (9) ◽  
pp. 772-800 ◽  
Author(s):  
Eva Mezeiova ◽  
Katarina Chalupova ◽  
Eugenie Nepovimova ◽  
Lukas Gorecki ◽  
Lukas Prchal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Inhibitor ◽  
Amyloid Β ◽  
Direct Interaction ◽  
Extensive Literature ◽  
Aβ Aggregation ◽  
Aggregation Inhibition ◽  
Approved Drugs

: Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.

Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer's Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Rohit Bhatia ◽  
Sankha Shubhra Chakrabarti ◽  
Upinder Kaur ◽  
Gaurav Parashar ◽  
Anindita Banerjee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Amyloid Β ◽  
Mao B ◽  
Clinical Investigations ◽  
Aβ Aggregation ◽  
Complex Events ◽  
Molecular Hybrids

: Alzheimer's disease (AD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cog- nitive domains, including executive function. The progression of AD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AD include a decreased concentration of acetylcholine (ACh), deposi- tion of amyloid-β (Aβ)peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid mole- cules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffolds have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aβ aggregation. In the present review, we have focused on different reported coumarin hy- brids as multi-target-directed agents against AD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hy- droxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hy- brids, important clinical investigations and the structure-activity relationship has also been discussed in this compilation.

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