Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(3), P. 654 - 672

Published: Feb. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Language: Английский

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Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Jan. 9, 2024

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly and represents a major clinical challenge ageing society. Neuropathological hallmarks AD include neurofibrillary tangles composed hyperphosphorylated tau, senile plaques derived from deposition amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) ubiquitously expressed central nervous system. Dysregulation DAPK1 has been shown to contribute various neurological diseases including AD, ischemic stroke Parkinson's (PD). We have established an upstream effect on Aβ tau pathologies apoptosis through kinase-mediated phosphorylation, supporting causal role pathophysiology AD. In this review, we summarize current knowledge about how involved pathological changes hyperphosphorylation, deposition, cell death degeneration. The underlying molecular mechanisms dysregulation are discussed. also review recent progress regarding development novel modulators their potential applications intervention. These findings substantiate as therapeutic target for multifunctional disease-modifying treatments other disorders.

Language: Английский

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Discovering potential ERK1 inhibitors from natural products for therapeutic targeting of Alzheimer's disease

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Background Extracellular signal-regulated kinase 1 (ERK1) belongs to mitogen-activated protein kinases, which are essential for memory formation, cognitive function, and synaptic plasticity. During Alzheimer's disease (AD), ERK1 phosphorylates tau at 15 phosphorylation sites, leading the formation of neurofibrillary tangles. The overactivation in microglia promotes release pro-inflammatory cytokines, results neuroinflammation. Additionally, elevated oxidative stress during AD stimulates pathway, neuronal loss. Objective Because signaling plays a significant role phosphorylation, targeting may be therapeutically beneficial by either preventing excessive activation pathway or altering its enhance neuroprotective effects AD. Methods This study employed structure-based virtual screening phytoconstituents from IMPPAT library. Subsequently, in-depth docking molecular dynamics (MD) simulation studies were implemented identify potential inhibitors with desirable pharmacological properties. Results Silandrin Hydroxytuberosone found higher affinity specificity than control molecule Tizaterkib. These compounds specifically bind substrate binding pocket interact crucial residues. Finally, elucidated evaluated using an all-atom MD analyze structural dynamics, compactness, hydrogen bond principal component analysis, free energy landscape. Conclusions suggested that can further exploited as lead molecules therapeutic development against ERK1-mediated

Language: Английский

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Posterior cingulate cortex microRNA dysregulation differentiates cognitive resilience, mild cognitive impairment, and Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract INTRODUCTION MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role miRNAs during progression AD, including resilience and prodromal syndromes such mild cognitive impairment (MCI), remains underexplored. METHODS We performed miRNA‐sequencing on samples posterior cingulate cortex (PCC) obtained post mortem from Rush Religious Orders Study participants diagnosed ante with no (NCI), MCI, or AD. NCI subjects were subdivided low pathology (Braak stage I/II) high III/IV), suggestive resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, AD risk modeling. RESULTS identified specific miRNA groups, mRNA targets, signaling distinguishing resilience, neuropsychological test performance, neuropathological burden, risk. DISCUSSION These findings highlight potential harnessing to manipulate disease‐modifying implications for precision medicine. Highlights (MiRNA) dysregulation well‐established feature Novel also distinguish putative MiRNAs correlate performance burden. Select are associated age significant covariate. MiRNA include insulin, prolactin, kinases, neurite plasticity.

Language: Английский

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Could protein phosphatase 2A and glycogen synthase kinase-3 beta be targeted by natural compounds to ameliorate Alzheimer’s pathologies?

Brain Research, Journal Year: 2024, Volume and Issue: 1829, P. 148793 - 148793

Published: Feb. 1, 2024

Language: Английский

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Design, synthesis, molecular docking, DFT analysis, dynamics simulation and cytotoxicity evaluation of coumarin derivatives as acetylcholinesterase (AChE) inhibitors against alzheimer's disease

Journal of Molecular Structure, Journal Year: 2025, Volume and Issue: unknown, P. 141436 - 141436

Published: Jan. 1, 2025

Language: Английский

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Design, Synthesis, and Bio-Evaluation of C2-Aryl Galantamine Derivatives

Published: Jan. 1, 2025

Language: Английский

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Polyoxometalates bind multiple targets involved in Alzheimer’s disease

JBIC Journal of Biological Inorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by brain aggregates of amyloid-β (Aβ) plaques and Tau tangles. Despite extensive research, effective therapy for AD remains elusive. Polyoxometalates (POMs), class inorganic compounds with diverse chemical structures properties, are emerging as potential candidates treatment due to their ability target key molecular players implicated in pathogenesis, such Aβ, acetylcholinesterase (AChE) butyryl (BChE). Here, we use docking predict the binding pose affinities POMs 10 top targets associated AD. First, validate our method replicating experimentally known Aβ (Δ G = – 9.67 kcal/mol), AChE 9.39 kcal/mol) BChE 10.86 kcal/mol). Then, using this method, show that POM can also bind β-secretase 1 (BACE1, Δ 10.14 presenilin (PSEN1, 10.65 2 (PSEN2, 7.94 Amyloid Precursor Protein (APP, 7.26 Apolipoprotein E (APOE4, 10.05 Microtubule-Associated (MAPT, 5.28 depending on phosphorylation, α-synuclein (SNCA, 7.64 Through binding, offer mitigate APP cleavage, oligomer neurotoxicity, aggregation, thereby attenuating progression. Overall, study represents powerful tool discovery POM-based therapeutics AD, facilitating development novel treatments Graphical abstract

Language: Английский

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Design, synthesis, and bio-evaluation of C1-aryl galantamine derivatives

Fitoterapia, Journal Year: 2025, Volume and Issue: 183, P. 106535 - 106535

Published: April 9, 2025

Language: Английский

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