GSK3: A potential target and pending issues for treatment of Alzheimer's disease.

Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3ß subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aß aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aß formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity-driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.

Anti-amyloid-ß Antibodies and Anti-tau Therapies for Alzheimer's Disease: Recent Advances and Perspectives.

Amyloid-ß (Aß) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to target Aß and tau have been the primary focus for several decades. Recently, substantial breakthroughs have been achieved in the clinical development of Aß antibodies; aducanumab was approved under conditional accelerated pathway by Food and Drug Administration (FDA) in the U.S. as the first disease-modifying agent for treating AD, and lecanemab has been granted traditional full approved in the U.S. and Japan. In addition, donanemab met the primary endpoint in a phase 3 study. On the other hand, tau-targeting therapies have failed to show clinical benefit although that increased tau levels show a strong correlation with cognitive impairment relative to Aß depositions. Currently, tau immunotherapies, such as anti-tau antibodies and tau vaccines, have shown functional benefits in clinical trials. Also, clinical trials for combination therapy of Aß and tau antibodies to see their potential are being investigated. In this review, we provide updates on the results of clinical trials of anti-Aß antibodies and anti-tau therapeutics and suggest future directions for these therapeutics.

Molecular Dynamics Simulation Study of the Self-Assembly of Tau-Derived PHF6 and Its Inhibition by Oleuropein Aglycone from Extra Virgin Olive Oil.

Alzheimer's disease (AD) and other taupathies are neurodegenerative disorders associated with the amyloid deposition of the Tau protein in the brain. This amyloid formation may be inhibited by small molecules, which is recognized as one of the best therapeutic strategies to stop the progression of the disease. This work focuses on the small nucleating segment, hexapeptide-paired helical filament 6 (PHF6), responsible for Tau aggregation. Using computational modeling and classical molecular dynamics simulations, we show that PHF6 monomers collapse in water to form ß-sheet rich structures, and the main olive oil polyphenol oleuropein aglycone (OleA) prevents peptide aggregation significantly. We gradually increase the ratio of the PHF6-OleA from 1:1 to 1:3 and find that for the 1:1 ratio, the peptide monomers are prone to form aggregated structures, while for the 1:2 ratio, the formation of the extended ß-sheet structure is significantly less. For a 1:3 ratio of protein/OleA, the peptide residues are sufficiently crowded by OleA molecules through hydrogen bonding, hydrophobic interactions, and π-π stacking; hence, the peptide chains prefer to exist in a monomeric random coil conformation.

Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.

Synthesis and biological evaluation of Halogen-Substituted novel α-Ketoamides as potential protein aggregation modulators in Alzheimer's disease.

The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aß) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from ß,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aß aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aß aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10-6 cm/s. In addition to its Aß inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aß induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.

How can we manage progressive supranuclear palsy syndrome with pharmacotherapy?

INTRODUCTION: Tauopathies are a spectrum of clinicopathological neurodegenerative disorders with increased aggregates included in glia and/or neurons of hyperphosphorylated insoluble tau protein, a microtubule-associated protein. Progressive supranuclear palsy (PSP) is an atypical dopaminergic-resistant parkinsonian syndrome, considered as a primary tauopathy with possible alteration of tau isoform ratio, and tau accumulations characterized by 4 R tau species as the main neuropathological lesions. AREAS COVERED: In the present review article, we analyzed and discussed viable disease-modifying and some symptomatic pharmacological therapeutics for PSP syndrome (PSPS). EXPERT OPINION: Pharmacological therapy for PSPS may interfere with the aggregation process or promote the clearance of abnormal tau aggregates. A variety of past and ongoing disease-modifying therapies targeting tau in PSPS included genetic, microtubule-stabilizing compounds, anti-phosphorylation, and acetylation agents, antiaggregant, protein removal, antioxidant neuronal and synaptic growth promotion therapies. New pharmacological gene-based approaches may open alternative prevention pathways for the deposition of abnormal tau in PSPS such as antisense oligonucleotide (ASO)-based drugs. Moreover, kinases and ubiquitin-proteasome systems could also be viable targets.

Role of Amyloidogenic and Non-Amyloidogenic Protein Spaces in Neurodegenerative Diseases and their Mitigation Using Theranostic Agents.

Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs.

The Unveiling of Therapeutic Targets for Alzheimer's Disease: An Integrative Review.

Alzheimer's disease (AD) is characterized by a complex pathological landscape, necessitating a comprehensive treatment approach. This concise review paper delves into the idea of addressing multiple mechanisms in AD, summarizing the latest research findings on pathogenesis, risk factors, diagnostics, and therapeutic strategies. The etiology of AD is multifaceted, involving genetic, environmental, and lifestyle factors. The primary feature is the accumulation of amyloid-- beta and tau proteins, leading to neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal loss. Conventional single-target therapies have shown limited effectiveness, prompting a shift toward simultaneously addressing multiple disease-related processes. Recent advancements in AD research underscore the potential of multifaceted therapies. This review explores strategies targeting both tau aggregation and amyloid-beta, along with interventions to alleviate neuroinflammation, enhance synaptic function, and reduce oxidative stress. In conclusion, the review emphasizes the growing importance of addressing various pathways in AD treatment. A holistic approach that targets different aspects of the disease holds promise for developing effective treatments and improving the quality of life for Alzheimer's patients and their caregivers.

A Comprehensive Review on Potential Molecular Drug Targets for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is an onset and incurable neurodegenerative disorder that has been linked to various genetic, environmental, and lifestyle factors. Recent research has revealed several potential targets for drug development, such as the prevention of Aß production and removal, prevention of tau hyperphosphorylation, and keeping neurons alive. Drugs that target numerous ADrelated variables have been developed, and early results are encouraging. This review provides a concise map of the different receptor signaling pathways associated with Alzheimer's Disease, as well as insight into drug design based on these pathways. It discusses the molecular mechanisms of AD pathogenesis, such as oxidative stress, aging, Aß turnover, thiol groups, and mitochondrial activities, and their role in the disease. It also reviews the potential drug targets, in vivo active agents, and docking studies done in AD and provides prospects for future drug development. This review intends to provide more clarity on the molecular processes that occur in Alzheimer's patient's brains, which can be of use in diagnosing and preventing the condition.

Functional Selection of Tau Oligomerization-Inhibiting Aptamers.

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3ß-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice.

Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.

Effective immunotherapy occurs in neurons.

Neuronal clearance of proteins in the brain proves to be important for immunotherapy.

De novo designed protein inhibitors of amyloid aggregation and seeding.

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-ß (Aß) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aß, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

Metformin in Alzheimer's disease: An overview of potential mechanisms, preclinical and clinical findings.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. The association between AD and other diseases such as diabetes is well-studied. In parallel, potential disease-modifying effects of therapeutic agents used for diabetes have been investigated in the context AD of. Metformin is a biguanide and the most commonly prescribed medication for type 2 diabetes Due to its pleiotropic properties, metformin's potential disease-modifying effects are widely studied on different pathophysiological plyers of AD such as amyloid-ß (Aß) production and clearance, tau phosphorylation, and neuroinflammation, in relevant in vitro and in vivo models. In this review, we summarize the relevant scientific literature on the effects of metformin on various aspects of AD pathophysiology.

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer's Disease.

BACKGROUND: Despite research on the molecular bases of Alzheimer's disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. METHODS: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. RESULTS: Our results demonstrated the increased bioactivity of three plants' metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. CONCLUSIONS: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.

Therapeutic potential of quinazoline derivatives for Alzheimer's disease: A comprehensive review.

Quinazolines are considered as a promising class of bioactive heterocyclic compounds with broad properties. Particularly, the quinazoline scaffold has an impressive role in the design and synthesis of new CNS-active drugs. The drug-like properties and pharmacological characteristics of quinazoline could lead to different drugs with various targets. Among CNS disorders, Alzheimer's disease (AD) is a progressive neurodegenerative disorder with memory loss, cognitive decline and language dysfunction. AD is a complex and multifactorial disease therefore, the need for finding multi-target drugs against this devastative disease is urgent. A literature survey revealed that quinazoline derivatives have diverse therapeutic potential for AD as modulators/inhibitors of ß-amyloid, tau protein, cholinesterases, monoamine oxidases, and phosphodiesterases as well as other protective effects. Thus, we describe here the most relevant and recent studies about anti-AD agents with quinazoline structure which can further aid the development and discovery of new anti-AD agents.

Cannabidiol Inhibits Tau Aggregation In Vitro.

A hallmark of Alzheimer's disease (AD) is the accumulation of tau protein in the brain. Compelling evidence indicates that the presence of tau aggregates causes irreversible neuronal destruction, eventually leading to synaptic loss. So far, the inhibition of tau aggregation has been recognized as one of the most effective therapeutic strategies. Cannabidiol (CBD), a major component found in Cannabis sativa L., has antioxidant activities as well as numerous neuroprotective features. Therefore, we hypothesize that CBD may serve as a potent substance to hamper tau aggregation in AD. In this study, we aim to investigate the CBD effect on the aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods in vitro and in silico. Using Thioflavin T (ThT) assay, circular dichroism (CD), and atomic force microscopy (AFM), we demonstrated that CBD can suppress tau fibrils formation. Moreover, by quenching assay, docking, and job's plot, we further demonstrated that one molecule of CBD interacts with one molecule of tau protein through a spontaneous binding. Experiments performed by quenching assay, docking, and Thioflavin T assay further established that the main forces are hydrogen Van der Waals and some non-negligible hydrophobic forces, affecting the lag phase of tau protein kinetics. Taken together, this study provides new insights about a natural substance, CBD, for tau therapy which may offer new hope for the treatment of AD.

Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core.

Tau aggregates represent a critical pathology in Alzheimer's disease (AD) and other forms of dementia. The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD. Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies. To evaluate the impact of the N-atom position with respect to Tau- and off-target binding, tricyclic core analogs of PI-2620 with nitrogen atoms at different positions were prepared. Affinity to aggregated Tau was evaluated using human AD brain homogenates, and their off-target binding was evaluated in a monoamine oxidase A (MAO-A) competition assay. The novel tricyclic core derivatives all displayed inferior Tau binding or MAO-A off-target selectivity, indicating PI-2620 to be the optimal design for high affinity binding to Tau and high MAO-A selectivity.

Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer's disease.

Development of multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for Alzheimer's disease (AD). Herein, we reported a new series of deoxyvasicinone analogues as dual inhibitor of acetylcholinesterase (AChE) and tau aggregation that function as multitargeted ligands for AD. All the multitargeted ligands 11(a-j) and 15(a-g) were designed, synthesized, and validated by 1HNMR, 13CNMR and mass spectrometry. All the synthesized compounds 11(a-j) and 15(a-g) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. All the screened compounds possessed weak inhibition of BACE-1, Aß42 and α-syn aggregation. However, several compounds were identified as potential hits in the AChE inhibitory screening assay and cellular tau aggregation screening. Among all compounds, 11f remarkably inhibited AChE activity and cellular tau oligomerization at single-dose screening (10 µM). Moreover, 11f displayed a half-maximal inhibitory concentration (IC50) value of 0.91 ± 0.05 µM and half-maximal effective concentration (EC50) value of 3.83 ± 0.51 µM for the inhibition of AChE and cellular tau oligomerization, respectively. In addition, the neuroprotective effect of 11f was determined in tau-expressing SH-SY5Y cells incubated with Aß oligomers. These findings highlighted the potential of 11f to function as a multifunctional ligand for the development of promising anti-AD drugs.