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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Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer’s disease in a large clinical sample

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Dec. 16, 2023

Abstract Alzheimer’s disease (AD) is a complex and heterogeneous neurodegenerative disorder with contributions from multiple pathophysiological pathways. One of the long-recognized important features AD disrupted cerebral glucose metabolism, but underlying molecular basis remains unclear. In this study, unbiased mass spectrometry was used to survey CSF large clinical cohort, comparing patients who are either cognitively unimpaired (CU; n = 68), suffering mild-cognitive impairment or dementia (MCI-AD, 95; DEM-AD, 72), other causes (MCI-other, 77; DEM-other, 23), Normal Pressure Hydrocephalus (NPH, 57). The results revealed changes related altered metabolism. particular, two glycolytic enzymes, pyruvate kinase (PKM) aldolase A (ALDOA), were found be upregulated in compared those neurological conditions. Increases full-length PKM ALDOA levels confirmed immunoblotting. Levels these enzymes furthermore correlated negatively matching samples. also increased publicly available brain-tissue data. These indicate that may act as technically-robust potential biomarkers metabolism dysregulation AD.

Language: Английский

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Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 12, 2024

Abstract Background Frontotemporal dementia (FTD) is the most common cause of early-onset with 10-20% cases caused by mutations in one three genes: GRN , C9orf72 or MAPT . To effectively develop therapeutics for FTD, identification and characterization biomarkers to understand disease pathogenesis evaluate impact specific therapeutic strategies on target biology as well underlying pathology are essential. Moreover, tracking longitudinal changes these throughout progression crucial discern their correlation clinical manifestations potential prognostic usage. Methods We conducted a comprehensive investigation indicative lysosomal biology, glial cell activation, synaptic neuronal health cerebrospinal fluid (CSF) plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) symptomatic carriers GRN, C9orf72, asymptomatic mutation carriers. also assessed Furthermore, we examined biomarker levels impacted brain regions including middle temporal gyrus (MTG) superior frontal (SFG) disease-unaffected inferior occipital (IOG) Results confirmed glucosylsphingosine (GlcSph), regulated progranulin, was elevated carriers, both asymptomatic. GlcSph other such ganglioside GM2 globoside GB3 were increased affected SFG MTG but not IOG, compared same controls. The GFAP YKL40 CSF all groups, except group. Neuronal injury degeneration NfL plasma, UCHL1 patients forms FTD. Synaptic NPTXR, NPTX1/2, VGF reduced pronounced reductions observed demonstrated significantly positively correlated severity measured CDR+NACC FTLD□SB genetic NPTXR negatively Conclusions In conclusion, our replicated alterations biofluid function, across unveiled novel insights into dysregulation within tissues mutations. correlations between open promising avenues applications indicators drug efficacy trials. Our data implicated complicated relationship tissue future investigations should delve mechanistic underpinnings biomarkers, which will serve foundation development targeted

Language: Английский

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Identification and Functional Validation of ACSL1 and FABP3 as Muscle-Related Genes Screened by Transcriptomics in Crossbred Duroc × Berkshire × Diannan Small-Eared Pigs

Genes, Journal Year: 2025, Volume and Issue: 16(5), P. 520 - 520

Published: April 29, 2025

Background: Crossbreeding strategies that combine the growth performance of Western pig breeds with meat quality traits Chinese indigenous have garnered considerable interest. Duroc pigs are known for their high efficiency but relatively low intramuscular fat (IMF) content. In contrast, native like Diannan Small-Eared exhibit superior pork higher IMF levels. This study aimed to compare muscle characteristics and molecular mechanisms between × Landrace Yorkshire (DLY) Berkshire (DBD) pigs. Methods: The longissimus dorsi tissue 210-day-old DLY DBD was collected analysis. HE staining assessed fiber characteristics, content measured, ELISA quantified muscle-derived development-related factors. Transcriptome sequencing conducted, followed by differential gene expression analysis, Gene Ontology (GO), Kyoto Encyclopedia Genes Genomes (KEGG), protein–protein interaction (PPI) analyses. Functional validation key genes performed in C2C12 cells. Results: exhibited significantly larger diameter compared IGF1 GH levels were elevated analysis identified 185 upregulated 102 downregulated genes, enrichment pathways including PI3K-Akt, MAPK, FoxO, cGMP-PKG signaling. ACSL1 FABP3 functionally validated, showing promotion differentiation inhibition proliferation Conclusions: may serve as regulators development

Language: Английский

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Screening Targets and Therapeutic Drugs for Alzheimer’s Disease Based on Deep Learning Model and Molecular Docking

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 100(3), P. 863 - 878

Published: July 12, 2024

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder caused by complex interplay of various factors. However, satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it paramount to search potential and drugs AD. Objective: We aimed provide novel treatment employing transcriptomic data normal control brain tissues from new perspective. Methods: Our study combined use multi-layer perceptron (MLP) with differential expression analysis, variance assessment molecular docking screen Results: identified seven differentially expressed genes (DEGs) significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, WDR49) in brain. A newly built MLP was used confirm association between DEGs AD, establishing these as targets. Drug databases results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, YC-1 had high affinity FABP3 bound oleic, palmitic, stearic acids. Arbaclofen activated GABAB receptor through PI3K/AKT PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect inhibiting p-tau Aβ formation. Conclusions: This provided strategy identification using deep learning. Seven ten were selected this method, providing insight treatment.

Language: Английский

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ROCK Inhibitor Fasudil Attenuates Neuroinflammation and Associated Metabolic Dysregulation in the Tau Transgenic Mouse Model of Alzheimer’s Disease

Current Alzheimer Research, Journal Year: 2024, Volume and Issue: 21(3), P. 183 - 200

Published: March 1, 2024

Background: The pathological manifestations of Alzheimer’s disease (AD) include not only brain amyloid β protein (Aβ) containing neuritic plaques and hyperphosphorylated tau (p-- tau) neurofibrillary tangles but also microgliosis, astrocytosis, neurodegeneration mediated by metabolic dysregulation neuroinflammation. Methods: While antibody-based therapies targeting Aβ have shown clinical promise, effective metabolism, neuroinflammation, p-tau are still an urgent need. Based on the observation that Ras homolog (Rho)-associated kinases (ROCK) activities elevated in AD, ROCK inhibitors been explored as AD models. This study determines effects fasudil, a inhibitor, neuroinflammation regulation P301S transgenic mouse line PS19 models neurodegenerative tauopathy AD. Using daily intraperitoneal (i.p.) delivery fasudil mice, we observed significant hippocampal-specific decrease levels phosphorylated (pTau Ser202/Thr205), GFAP+ cells glycolytic enzyme Pkm1 broad regions brain, mitochondrial complex IV subunit I striatum thalamic regions. Results: Although no overt detrimental phenotype was observed, mice dosed with 100 mg/kg/day for 2 weeks exhibited significantly decreased outer membrane electron transport chain (ETC) abundance, well ETC activities. Conclusion: Our results provide insights into dose-dependent neuroinflammatory responses to support further refinement treatment

Language: Английский

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Identification of the Shared Gene Signatures Between Alzheimer’s Disease and Diabetes-Associated Cognitive Dysfunction by Bioinformatics Analysis Combined with Biological Experiment

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 101(2), P. 611 - 625

Published: Aug. 30, 2024

Background: The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer’s disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related. Objective: To explore shared genes pathways DACD AD using bioinformatics analysis combined with biological experiment. Methods: We analyzed GEO microarray data identify DEGs type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network was used find modules, while R packages identified overlapping genes. A robust protein-protein interaction constructed, hub were Gene ontology enrichment Kyoto Encyclopedia of Genome pathway analyses. HT22 cells cultured under high glucose amyloid-β 25–35 (Aβ25-35) conditions establish models. Quantitative polymerase chain reaction reverse transcription verification then performed on intersection Results: Three modules each T2DM most relevant 10 screened, revealing such synaptic vesicle cycle GABAergic synapse. Through experimentation verification, 6 key identified. Conclusions: This study is first use tools uncover genetic link DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, SH3GL2 connecting These findings offer new insights into diseases’ pathogenesis potential diagnostic therapeutic targets.

Language: Английский

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Defining Alzheimer’s Disease through Proteomic CSF Profiling

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(11), P. 5096 - 5106

Published: Oct. 7, 2024

Alzheimer disease (AD) is the main cause of dementia, and its complexity not yet completely understood. Proteomic profiles can provide useful information to explore pathways involved heterogeneity among AD patients. A proteomic analysis was performed in cerebrospinal fluid (CSF) samples from mild cognitive impairment due (MCI-AD) control individuals; both groups were classified by amyloid β42/amyloid β40 levels CSF (data available BioStudies database (S-BSST1456)). The based on PLS regression volcano plot identified 7 proteins (FOLR2, PPP3CA, SMOC2, STMN1, TAGLN3, TMEM132B, UCHL1) mainly related protein phosphorylation, structure maintenance, inflammation, degradation. Enrichment revealed involvement different biological processes neuronal mechanisms synapses, lipid carbohydrate metabolism, immune system vascular, hormones, response stimuli, cell signaling adhesion. In addition, profile showed some association with biomarkers CSF. Regarding subtypes, two MCI-AD subgroups identified: one could be synapsis functions other innate immunity. study patients reflects biochemical AD.

Language: Английский

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