Potential Therapeutic Strategies for Alzheimer’s Disease Targeting or Beyondβ-Amyloid: Insights from Clinical Trials

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with two hallmarks:β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer’s disease.

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A Nanoinformatics Approach to Evaluate the Pharmacological Properties of Nanoparticles for the treatment of Alzheimer’s Disease

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210217145733 ◽

2021 ◽

Vol 24 ◽

Author(s):

Muhammad Zohaib Nawaz ◽

Syed Awais Attique ◽

Qurat-ul-Ain ◽

Fahdah Ayed Alshammari ◽

Heba Waheeb Alhamdi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Carbon Nanotubes ◽

Alzheimer's Disease ◽

Nervous System ◽

Drug Targets ◽

Kinase Domain ◽

New Drugs ◽

Drug Candidates ◽

Experimental Approaches ◽

Novel Drug

Background: Alzheimer’s disease is a nervous system destructive disease which causes structural, biochemical and electrical abnormalities inside the human brain and results due to genetic and various environmental factors. Traditional therapeutic agents of Alzheimer’s disease such as tacrine and physostigmine has been found causing adverse effects to the nervous system and gastrointestinal tract. Nanomaterials like graphene, metals, carbon-nanotubes and metal-oxides are gaining attention as potential drugs against Alzheimer’s disease due to their properties such as large surface area which provides clinical efficiency, targeted drug designing and delivery. Objectives: Designing new drugs by using experimental approaches are time-consuming, tedious and laborious processes which also require advanced technologies. This study aims to identify the novel drug candidates against Alzheimer’s disease with no or less associated side effects using molecular docking approaches. Methods: In this study, we utilized nanoinformatics based approaches for evaluating the interaction properties of various nanomaterials and metal nanoparticles with the drug targets including TRKB kinase domain, EphA4 and histone deacetylase. Furthermore, drug-likeness of carbon nanotubes was confirmed through ADME analysis. Results: Carbon nanotubes, either single or double-walled in all the three-configuration including zigzag, chiral, and armchair forms are found to interact with the target receptors with varying affinities. Conclusion: This study provides a novel and clearer insights into the interaction properties and drug suitability of known putative nanoparticles as potential agents for the treatment of Alzheimer’s disease.

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Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

Current Molecular Pharmacology ◽

10.2174/1874467213666200422090135 ◽

2020 ◽

Vol 13 (4) ◽

pp. 273-294 ◽

Cited By ~ 2

Author(s):

Elahe Zarini-Gakiye ◽

Javad Amini ◽

Nima Sanadgol ◽

Gholamhassan Vaezi ◽

Kazem Parivar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Small Molecules ◽

Clinical Trial Design ◽

Treatment Approaches ◽

Drug Candidates ◽

Novel Treatments ◽

Approved Drugs ◽

Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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Neurobiochemical Cross-talk Between COVID-19 and Alzheimer’s Disease

Molecular Neurobiology ◽

10.1007/s12035-020-02177-w ◽

2020 ◽

Cited By ~ 1

Author(s):

Mohammad Azizur Rahman ◽

Kamrul Islam ◽

Saidur Rahman ◽

Md Alamin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Markers ◽

Interleukin 1 ◽

Therapeutic Strategies ◽

Therapeutic Approaches ◽

Angiotensin Converting Enzyme 2 ◽

Apoe4 Allele ◽

The Common ◽

Global Threat

Abstract COVID-19, the global threat to humanity, shares etiological cofactors with multiple diseases including Alzheimer’s disease (AD). Understanding the common links between COVID-19 and AD would harness strategizing therapeutic approaches against both. Considering the urgency of formulating COVID-19 medication, its AD association and manifestations have been reviewed here, putting emphasis on memory and learning disruption. COVID-19 and AD share common links with respect to angiotensin-converting enzyme 2 (ACE2) receptors and pro-inflammatory markers such as interleukin-1 (IL-1), IL-6, cytoskeleton-associated protein 4 (CKAP4), galectin-9 (GAL-9 or Gal-9), and APOE4 allele. Common etiological factors and common manifestations described in this review would aid in developing therapeutic strategies for both COVID-19 and AD and thus impact on eradicating the ongoing global threat. Thus, people suffering from COVID-19 or who have come round of it as well as people at risk of developing AD or already suffering from AD, would be benefitted.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21165858 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5858 ◽

Cited By ~ 3

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.

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Full-length and C-terminal neurogranin in Alzheimer’s disease cerebrospinal fluid analyzed by novel ultrasensitive immunoassays

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00748-6 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Annika Öhrfelt ◽

Julien Dumurgier ◽

Henrik Zetterberg ◽

Agathe Vrillon ◽

Nicholas J. Ashton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Molecule ◽

Full Length ◽

The Novel ◽

Drug Candidates ◽

Postsynaptic Protein ◽

Coefficients Of Variation ◽

Assay Precision ◽

Novel Drug

Abstract Background Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer’s disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease. Methods In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26). Results The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785). Conclusions Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.

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Drugs for Targeted Therapies of Alzheimer’s Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666180430150940 ◽

2019 ◽

Vol 26 (2) ◽

pp. 335-359 ◽

Cited By ~ 4

Author(s):

Chit Tam ◽

Jack Ho Wong ◽

Tzi Bun Ng ◽

Stephen Kwok Wing Tsui ◽

Tao Zuo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Drug Targets ◽

The Elderly ◽

Dependent Manner ◽

Cell Replacement Therapy ◽

Drug Candidates ◽

Amyloid A ◽

Potential Drug Targets

Alzheimer’s disease (AD) is one type of neurodegenerative diseases, which is prevalent in the elderly. Beta-amyloid (Aβ) plaques and phosphorylated tau-induced neurofibrillary tangles are two pathological hallmarks of this disease and the corresponding pathological pathways of these hallmarks are considered as the therapeutic targets. There are many drugs scheduled for pre-clinical and clinical trial that target to inhibit the initiators of pathological Aβ and tau aggregates as well as critical Aβ secretases and kinases in tau hyperphosphorylation. In addition, studies in disease gene variations, and detection of key prognostic effectors in early development are also important for AD control. The discovery of potential drug targets contributed to targeted therapy in a stage-dependent manner, However, there are still some issues that cause concern such as the low bioavailability and low efficacy of candidate drugs from clinical trial reports. Therefore, modification of drug candidates and development of delivery agents are essential and critical. With other medical advancements like cell replacement therapy, there is hope for the cure of Alzheimer’s disease in the foreseeable future.

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Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/386527 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 60

Author(s):

Sergio Davinelli ◽

Nadia Sapere ◽

Davide Zella ◽

Renata Bracale ◽

Mariano Intrieri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Protective Effects ◽

Drug Candidates ◽

Molecular Events ◽

Therapeutic Value ◽

Phytochemical Compounds ◽

Multiple Levels ◽

The Brain

Alzheimer’s disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

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Exploring Aβ Proteotoxicity and Therapeutic Candidates Using Drosophila melanogaster

International Journal of Molecular Sciences ◽

10.3390/ijms221910448 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10448

Author(s):

Greta Elovsson ◽

Liza Bergkvist ◽

Ann-Christin Brorsson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drosophila Melanogaster ◽

Model Organism ◽

Amyloid Β ◽

Therapeutic Strategies ◽

Disease Genes ◽

Amyloid Β Peptide ◽

Drug Candidates ◽

Human Disease Genes

Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is able to uncover anti-proteotoxic candidates due to its outstanding genetic toolbox and resemblance to human disease genes. In this review, we highlight the use of Drosophila melanogaster to both study the proteotoxicity of the amyloid-β peptide and to screen for drug candidates. Expanding the knowledge of how the etiology of Alzheimer’s disease is related to proteotoxicity and how drugs can be used to block disease progression will hopefully shed further light on the field in the search for disease-modifying treatments.

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Multitarget Approach to Drug Candidates against Alzheimer’s Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets

Molecules ◽

10.3390/molecules25081846 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1846

Author(s):

Larisa Ivanova ◽

Mati Karelson ◽

Dimitar A. Dobchev

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Experimental Testing ◽

Drug Candidate ◽

Multilinear Regression ◽

Protein Targets ◽

Drug Candidates ◽

Multifunctional Compounds ◽

Contemporary Medicine ◽

Effective Drugs

Alzheimer’s disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer’s disease, new and more effective drugs are in great demand. In this work, we proposed three potential drug candidates which may act as multifunctional compounds simultaneously toward AChE, SERT, BACE1 and GSK3β protein targets. These candidates were discovered by using state-of-the-art methods as molecular calculations (molecular docking and molecular dynamics), artificial neural networks and multilinear regression models. These methods were used for virtual screening of the publicly available library containing more than twenty thousand compounds. The experimental testing enabled us to confirm a multitarget drug candidate active at low micromolar concentrations against two targets, e.g., AChE and BACE1.

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Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?

Molecules ◽

10.3390/molecules24081519 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1519 ◽

Cited By ~ 19

Author(s):

Habtemariam

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Therapeutic Approaches ◽

Mediated Effects ◽

Pharmacological Targets ◽

Disease Therapy ◽

Therapeutic Principles ◽

Novel Drug ◽

Ad Therapy

Despite extensive progress in understanding the pathology of Alzheimer’s disease (AD) over the last 50 years, clinical trials based on the amyloid–beta (Aβ) hypothesis have kept failing in late stage human trials. As a result, just four old drugs of limited clinical outcomes and numerous side effects are currently used for AD therapy. This article assesses the common pharmacological targets and therapeutic principles for current and future drugs. It also underlines the merits of natural products acting through a polytherapeutic approach over a monotherapy option of AD therapy. Multi-targeting approaches through general antioxidant and anti-inflammatory mechanisms coupled with specific receptor and/or enzyme-mediated effects in neuroprotection, neuroregeneration, and other rational perspectives of novel drug discovery are emphasized.

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