Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices

Frontiers in Neuroanatomy, Journal Year: 2025, Volume and Issue: 19

Published: April 4, 2025

Expression of the N-methyl-D-aspartate receptor, particularly when containing GluN2B subunit (NMDAR-GluN2B), varies across prefrontal cortex (PFC). In humans, subgenual cingulate (SGC) contains among highest levels NMDAR-GluN2B expression, while dorsolateral (dlPFC) exhibits a more moderate level expression. are commonly associated with ionotropic synaptic function and plasticity essential to neurotransmission underlying working memory in macaque dlPFC layer III circuits, which humans afflicted schizophrenia. However, can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked neurodegenerative processes. The SGC is an early site tau pathology sporadic Alzheimer’s disease (sAD), mirrors its high Additionally, hyperactive depression, treated NMDAR antagonists. Given clinical relevance dlPFC, current study used immunoelectron microscopy (immunoEM) quantitatively compare expression patterns excitatory inhibitory neuron dendrites rhesus dlPFC. We larger population putative pyramidal neurons as compared had higher proportion NMDAR-GluN2B. contrast, from both areas, was far frequently observed over These findings provide insight into varying cortical vulnerability alterations excitability forces.

Language: Английский

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Ionic and Non-Ionic Counterparts Based on Bis(Uracilyl)Alkane Moiety with Highest Selectivity Towards Acetylcholinesterase for Protection Against Organophosphate Poisoning and Treating Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3759 - 3759

Published: April 16, 2025

A series of bisuracils, in which uracil and 3,6-dimethyluracil moieties were bridged with a polymethylene spacer, the moiety contained pentamethylene radical ionic non-ionic aminobenzyl groups, synthesised. These bisuracils have been identified as cholinesterase inhibitors exceptional selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). highly effective AChE inhibitors, demonstrated activity at nano- sub-nanomolar concentrations, BuChE. In kinetic studies lead 2b 3c, both compounds exhibited mixed-type inhibition against Additionally, molecular dynamic simulations robust stable interactions 3c binding sites their target. Bisuracil showed significant potential protection from irreversible by paraoxon; most dose 0.01 mg/kg was shown to reduce mortality paraoxon-poisoned mice. effectively inhibited brain activity, reversing scopolamine-induced amnesia mice 5 mg/kg, indicates its cognitive enhancement. findings position promising prophylactics organophosphate poisoning viable candidates Alzheimer’s disease therapeutics.

Language: Английский

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Anticorps monoclonaux anti-amyloïde Beta contre la maladie d’Alzheimer en 2025 : prudence ou scepticisme ?

Bulletin de l Académie Nationale de Médecine, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

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Development and Application of an In-Capillary CE-DAD Method for the Inhibitory Screening of Natural Extracts Towards Acetylcholinesterase Enzyme

Metabolites, Journal Year: 2025, Volume and Issue: 15(4), P. 283 - 283

Published: April 18, 2025

Background: The enzymatic activity of acetylcholinesterase (AChE) has been a focal point in neurodegenerative diseases research, particularly relation to Alzheimer’s disease. This is attributed the significantly reduced levels cholinergic neurons observed patients compared healthy individuals. strategy mitigate onset these lies exploration new potential AChE inhibitors with focus also on natural extracts. A rapid and specific capillary electrophoresis method direct ultraviolet detection (CZE-UV/Vis) was developed screen extracts by assessing their inhibit AChE. Materials Methods: To enhance specificity when analysing complex matrixes such as extracts, sequential analysis approach based “sandwich model” implemented using Ellman’s reagent [5,5′-dithiobis-(2-nitrobenzoic acid)] (DTNB) colorimetric indicator. Results: reference inhibitor, neostigmine, used for system validation through IC50 Ki values determination subsequent injections acetylthiocholine substrate presence neostigmine at increasing concentrations, enzyme combined DTNB borate-phosphate buffer (30 mM, pH 8.0). product selectively detected 412 nm. validated applied seven Conclusions: Results demonstrated promising outcomes identifying phytotherapeutic agents applications prevention diseases. provides high selectivity automation, offering streamlined effective screening matrices containing inhibitors.

Language: Английский

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Subtle Alterations in Hippocampal Neuronal Activity Coincide With Early Sex‐Specific Differences in Amyloidosis and Microglia in a Pre‐Symptomatic Mouse Model of Alzheimer‐Like Pathology

Glia, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

ABSTRACT Growing evidence highlights sex‐related differences in the pathogenesis of Alzheimer's disease (AD). Yet, early impact sex on neuronal activity and microglia hippocampus, a main site memory formation one most vulnerable brain areas AD, remains poorly understood. We thus assessed these issues by using APPPS1 mouse model AD‐like amyloid pathology at pre‐symptomatic stage (5–6 months). Our electrophysiological data point to opposite alterations hippocampal CA1 neurons' basal glutamatergic neurotransmission response excitatory inputs between male female mice. These complex changes are likely precede plasticity impairments, which do not yet translate into sexual dimorphism Long‐Term Potentiation (LTP) studied age. Alteration synaptic transmission males coincides with an increased number coverage microglia, together plaque coverage, as compared hippocampus. Such microgliosis is accompanied expression specific transcriptomic markers Disease‐Associated Microglia (DAM)/Microglial neurodegenerative phenotype (MGnD), whereas homeostatic (M0) were unaffected. show for first time that subtle coincide amyloidosis already pathology.

Language: Английский

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N-N-Substituted Piperazine, Cmp2, Improves Cognitive and Motor Functions in 5xFAD Mice

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(10), P. 4591 - 4591

Published: May 10, 2025

The piperazine derivative N-(2,6-difluorophenyl)-2-(4-phenylpiperazin-1-yl)propanamide (cmp2) has emerged as a potential transient receptor cation channel, subfamily C, member 6 (TRPC6) modulator, offering promising pathway for Alzheimer’s disease (AD) therapy. Our recent findings identify cmp2 novel compound with synaptoprotective effects in primary hippocampal cultures and effective blood–brain barrier (BBB) penetration. In vivo studies demonstrate that (10 mg/kg, intraperitoneally) restores synaptic plasticity deficits 5xFAD mice. This study further shows cmp2’s selectivity towards tetrameric TRPC6 channel silico. Acute administration of is non-toxic, no indications chronic toxicity, Ames testing confirms its lack mutagenicity. Behavioral assays reveal improves cognitive functions mice, including increased object recognition, better passing the Morris water maze, improved fear memory, well upregulation motor function beam walking tests. These suggest holds promise candidate AD treatment.

Language: Английский

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Harnessing Essential Oils for Acetylcholinesterase Inhibition: A Literature Review

Phytotherapy Research, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

ABSTRACT Aromatherapy, a branch of herbal and alternative medicine, has emerged as promising non‐pharmacological approach to treating Alzheimer's disease (AD) due its potential enhance cognitive function. This comprehensive review evaluates the inhibitory effects various plant essential oils (EOs) on acetylcholinesterase (AChE) activity, key enzyme implicated in pathophysiology AD. Our analysis highlights EOs from Lamiaceae family, particularly rosemary ( Salvia rosmarinus ) lavender Lavandula officinalis ), which demonstrated most potent AChE effects. Key chemical constituents such α‐ β‐pinene, limonene, linalool, 1,8‐cineole, caryophyllene, estragole, eugenol, asarone were identified primary active components responsible for these Additionally, we discuss biochemical mechanisms underlying neuroprotective properties their role developing effective therapies findings underscore therapeutic promise specific managing decline associated with neurodegenerative disorders.

Language: Английский

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Nanocarrier-based targeted drug delivery for Alzheimer’s disease: addressing neuroinflammation and enhancing clinical translation

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: May 14, 2025

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-beta (Aβ) aggregation, tau pathology, and chronic neuroinflammation. Among these, neuroinflammation plays crucial role in exacerbating progression, making it an attractive therapeutic target. However, the presence of blood-brain barrier (BBB) significantly limits effective delivery agents to brain, necessitating novel drug strategies. Nanocarrier-based systems have emerged as promising solution these challenges, offering targeted transport, enhanced BBB penetration, improved bioavailability while minimizing systemic toxicity. This review explores current advancements nanocarrier-mediated for AD, focusing on mechanisms neuroinflammation, nanocarriers overcoming BBB, their ability modulate inflammatory pathways. Furthermore, discusses preclinical validation strategies key including safety concerns, large-scale production limitations, regulatory hurdles that must be addressed enable clinical translation. Future perspectives emphasize integration nanotechnology with precision medicine, gene therapy, artificial intelligence optimize nanocarrier design individualized AD treatment. By obstacles, hold potential revolutionize approaches other diseases.

Language: Английский

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Caveolae with serotonin and NMDA receptors as promising targets for the treatment of Alzheimer’s disease

International Journal of Physiology Pathophysiology and Pharmacology, Journal Year: 2024, Volume and Issue: 16(5), P. 96 - 110

Published: Jan. 1, 2024

Alzheimer's disease is the most general type of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained more elusive. Consequently, research direction should be for finding effective neuroprotective agents. It has been suggested oxidative stress, mitochondrial injury, and inflammation level might lead to brain cell death in many neurological disorders. Therefore, several autophagy-targeted bioactive compounds may promising candidate therapeutics prevention damage. Interestingly, some risk genes are expressed within cells, which linked cholesterol metabolism, lipid transport, endocytosis, exocytosis and/or caveolae formation, suggesting a fruitful therapeutic target improve This review would highlight latest advances technologies treatment disease. In particular, paradigm serotonin N-methyl-d-aspartate (NMDA) receptors agonist/antagonist structure possibly impairment. cellular membrane biophysics our understanding pathology dysfunction associated with Here, this purpose therapy open potential move care toward disease-modifying certain benefits patients.

Language: Английский

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Cholinesterase Inhibitory Activity of Paeoniflorin: Molecular Dynamics Simulation, and In Vitro Mechanistic Investigation

Biochemistry Research International, Journal Year: 2024, Volume and Issue: 2024(1)

Published: Jan. 1, 2024

Alzheimer’s disease (AD), a neurological disorder, is one of the major reasons for memory loss in world. AD characterized by sequela cognitive and functional decline caused brain cell degeneration. Paeoniflorin monoterpenoid glycoside found plants Paeoniaceae family, which are known their medicinal properties including dementia. In this project, we report actions paeoniflorin on two related cholinesterases (ChE): acetylChE (AChE) butyrylChE (BuChE). Paeoniflorin, dose‐dependent (maximum inhibition at 1 mg/mL) manner, inhibited both AChE (0.06–1 BuChE (0.007–1 enzymes with maximum enzyme 90.3 ± 1.4%, while 99.4 0.3% enzyme. The EC 50 value inhibitory effect compound against was 0.52 mg/mL (0.18–1.52), 0.13 (0.08–0.21). observed ani‐ChE action like an also mediated ChE blocker physostigmine. Molecular interactions between were additionally sought via molecular docking dynamics simulations 100 ns, that showed interacted active‐site gorge hydrogen bonds water bridging many amino acids enzymes. This study presents potential With kind activity, chemical can potentially increase ACh levels may have use treatment dementia AD.

Language: Английский

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