ACS Chemical Neuroscience最新文献

Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer’s disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.

Neuroinflammation is evident in Alzheimer’s disease (AD) brains, exacerbating the pathology and ensuing cognitive deficits in patients. The prostaglandin-E2 receptor EP2 emerged as a neuroinflammatory target in several neurodegenerative diseases, including AD. Antagonism of EP2 mitigates neuroinflammation and cognitive deficits in status epilepticus and stroke models. Here, we investigated the efficacy of a potent and selective EP2 antagonist TG11–77.HCl on the cognitive behavior and neuroinflammation in a two-hit 5xFAD mouse model of AD. We exposed adult 5xFAD mice on B6SJL genetic background and their nontransgenic littermates to a low dose of lipopolysaccharide and administered TG11–77.HCl or the vehicle in the drinking water for 12 weeks. Mice were subjected to Morris water maze and Y-maze testing during their last week of drug treatment. Blood samples were subjected to complete blood count (CBC) analysis and brain tissues were processed to examine the levels of inflammatory transcripts and glial marker expression (mRNA), followed by the quantification of congophilic amyloid deposition and microglial activation (IBA⁺) in the brain by immunohistochemistry. TG11–77.HCl treatment enhanced the spatial memory performance and ameliorated mRNA expression of proinflammatory mediators, chemokines, and cytokines in the neocortex of 5xFAD males only and attenuated astroglia and microglia activation in both male and female 5xFAD mice and the congophilic amyloid load in 5xFAD males only. CBC analysis revealed no changes in peripheral inflammation, irrespective of sex, on treatment with TG11–77.HCl. This study reveals sex-specific protection of selective EP2 antagonism in a two-hit mouse model of AD and supports a prudent therapeutic strategy against neuroinflammation and associated cognitive impairment in AD.

The distinct subjective effects that define psychedelics such as lysergic acid diethylamide (LSD), psilocybin, or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) as drug class are causally linked to the activation of the serotonin 2A receptor (5-HT_2AR). However, some aspects of 5-HT_2AR pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from nonpsychedelic 5-HT_2AR agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT_2AR engagement of the canonical G_q/11 pathway in native tissue. This nonradioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP₁) in the mouse brain. The specificity of this method was assessed in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT_2AR knockout (5-HT_2AR-KO) animals compared to other brain regions, namely, striatum and cerebellum. The effect of DOI on mouse frontal cortex IP₁ was time-bound, dose-dependent, and was correlated to head twitch response counts. We observed that IP₁ levels in frontal cortex homogenates from mice treated with LSD and lisuride varying in magnitude, consistent with LSD’s 5-HT_2AR agonism and psychedelic nature and lisuride’s lack thereof. 3,4-Methylenedioxymethamphetamine (MDMA) evoked an increase in the IP₁ signal in the frontal cortex that was not matched by the serotonin precursor 5-hydroxytryptophan or the serotonin reuptake inhibitor fluoxetine. We attribute the differences in the readout primarily to the indirect stimulation of 5-HT_2AR by MDMA via the release of serotonin from its presynaptic terminals. This methodology enables one to capture a snapshot of IP₁ turnover in the mouse brain that can provide mechanistic insights into the study of psychedelics and G_q/11-coupled receptors.

This study explores novel multitarget-directed ligands (MTDLs) showing anticholinesterase, antioxidant, neuroprotective, and calcium channel inhibitory activities, as promising compounds for Alzheimer’s disease (AD) treatment. The rational design combined dihydropyridines (DHPs), known for calcium channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. The key innovation of this work lies in the one-pot tandem Hantzsch multicomponent/click reaction used to synthesize new 18 DHPs IIIa-r. This sustainable and original approach aligns with green chemistry principles by reducing waste, energy consumption, and derivatives formation. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry.

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder characterized by severe motor symptoms. While the degeneration of dopaminergic neurons in the substantia nigra plays a central role, other neurotransmitter systems also contribute to PD symptoms. α-Synuclein (αSyn), normally expressed in neurons to support synaptic function and neurotransmitter release, becomes pathologically accumulated in PD, despite not being upregulated under physiological conditions. Intracellular aggregation of αSyn into Lewy bodies is a hallmark of synucleinopathies. A vital facet of both the onset and progression of PD involves mitochondrial dysfunction, which links αSyn misimport into mitochondria with neuronal death. The interaction of αSyn with mitochondrial membranes has been identified, yet the complex stepwise biological mechanisms of αSyn misimport into the mitochondrial compartments, followed by its aggregation, culminating in mitochondria-mediated apoptosis, remain unknown. The Translocase of the Outer Mitochondrial Membrane (TOM) complex, vital for unidirectional import of >1300 mitochondrial proteins from the cytosol, can additionally misimport αSyn into mitochondria. This TOM−αSyn interplay can alter calcium homeostasis, reduce ATP biogenesis, elevate reactive oxygen species generation, and compromise mitochondrial dynamics, resulting in mitochondrial dysfunction and triggering cell death in dopaminergic neurons. Detailed analyses of TOM complex function, interactome, and TOM−αSyn association could lead to treatment approaches that restore mitochondrial homeostasis by mitigating the effects of αSyn pathology in neurodegenerative conditions. This review details the most recent findings on independent regulators of αSyn and the TOM complex and discusses TOM−αSyn interaction mechanisms and their outcomes on mitochondrial dynamics toward promoting development of therapeutics for neurodegeneration.

Synucleinopathies are a group of neurodegenerative disorders characterized by structural aberrations in the protein alpha-synuclein (α-syn). In these disorders, α-syn accumulates and misfolds, contributing to the formation of intracellular inclusion bodies believed to precede cellular death. We investigated the capacity of cardiolipin (CL)-based nanoparticles to reverse α-syn fibrillization, and rescue loss of dopamine neurons. Using circular dichroism (CD) and transmission electron microscopy (TEM), we assessed conformational changes in α-syn upon interaction with CL-nanoparticles. Combined with functional assessment of CL-nanoparticles in rodent models of synucleinopathy, we demonstrate that CL nanoparticles induced structural refolding of fibrillar α-syn toward a monomeric α-helical form, dissolving α-syn aggregates and rescuing from cell death. Thus, CL-based nanoparticles may represent a therapeutic tool to mitigate synucleinopathy.

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy (SMEI), is an intractable epilepsy syndrome. Most cases are associated with mutations in the SCN1A gene, which is responsible for the expression of the sodium voltage-gated channel alpha subunit 1, Nav1.1. These mutations lead to altered neuronal firing and a state of hyperexcitability. DS has been studied using patient samples, animal models, and more recently, iPS cells derived from DS patients. In this work, we sought to understand the impact that Nav1.1 loss-of-function has on the elementary chemical constitution of DS patient-derived neural cells. iPS cells from DS patients and controls were differentiated into neural-induced spheroids, and synchrotron X-ray radiation was used to assess alterations in their elemental concentration. We observed that DS-derived neural cells present elevated levels of potassium (K), copper (Cu), and zinc (Zn). These findings suggest that an elemental imbalance may be involved in the pathogenesis of DS, as higher levels of K, Cu, and Zn have been implicated in seizure episodes and epilepsy. We conclude that modeling DS using cell reprogramming is a relevant approach to understanding the basic mechanisms involved in this disease and perhaps provide novel treatment strategies.

The adenosine A_2A receptor (A_2AAR) is implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, due to its involvement in neuroinflammatory processes and synaptic function. However, suitable positron emission tomography (PET) radioligands for direct imaging of A_2AAR in the living brain remain limited. In this study, we describe the synthesis and preclinical evaluation of [¹¹C]2, a novel PET radioligand developed to target A_2AAR with moderate affinity and selectivity. [¹¹C]2 was synthesized with high radiochemical purity and satisfactory molar activity. In vivo PET imaging in wild-type mice demonstrated that [¹¹C]2 efficiently crossed the blood–brain barrier and distributed throughout the brain. Blocking studies with unlabeled compound 2 confirmed the specificity of [¹¹C]2 binding in vivo. In vitro autoradiography further revealed regional binding patterns in both wild-type and Alzheimer’s disease model mice. Slightly higher in vitro signals in AD model mice suggest a potential link to neuroinflammatory mechanisms, although further investigation is required. Notably, during the initial 0.5–2.5 min after injection, striatal uptake was modestly higher than in other brain regions; however, this advantage became indistinct at later time points. Thus, while [¹¹C]2 enables very early phase mapping of A_2AAR distribution, the transient nature of its striatal preference indicates that further structural optimization is required to enhance sustained striatal selectivity and overall imaging performance.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by complex genetic and molecular interactions. Despite major advances in genomics, current discoveries explain less than 40% of AD heritability, underscoring the need for integrative approaches that capture cross-omic regulation. Here, we propose a multiomics integration framework combining genomic, epigenomic, and transcriptomic data sets to identify convergent molecular signatures underlying AD pathogenesis. An integrated epigenome-wide association study-genome wide association study (EWAS–GWAS) analysis using GeneCards and VarElect identified 42 candidate genes, showing overlap between genetic susceptibility and epigenetic dysregulation. These include canonical AD loci (APOE, CLU, BIN1, PICALM, and TREM2) and novel regulatory genes such as AKT1, DOT1L, SREBF1, and PVT1. Network analysis revealed 32 nodes and 30 edges with an average node degree of 1.88 and a protein–protein interaction (PPI) enrichment p-value of 6.45 × 10^–6, indicating significant functional connectivity. Integrative pathway mapping highlighted mitochondrial–nuclear cross-talk, metabolic dysfunction, and noncoding RNA regulation as central pathogenic axes. This multilayered approach bridges static genomic variants with dynamic epigenetic and transcriptomic alterations, offering a systems-level view of disease mechanisms. Methodologically, the framework integrates EWAS–GWAS correlation, functional annotation, and PPI modeling to prioritize biologically relevant targets. Translationally, these findings reveal potential methylation-based biomarkers, polygenic–epigenetic risk models, and targetable molecular pathways for early detection and precision therapeutics. Overall, this integrative strategy enhances mechanistic understanding and supports the development of predictive, multiomic tools for individualized AD management.