ACS Chemical Neuroscience最新文献

The causes of neurodegeneration remain elusive. There is growing evidence linking viral infection to dysregulated neurotransmission as a causative factor in Alzheimer’s disease. Studies suggest that viral infection may result in dysregulated glutamatergic and l-arginine/NO neurotransmission that can initiate neurodegeneration and neuroinflammation within AD. This involves viral infection (HIV-1/HSV-1) altering glutamate biosynthesis and receptor activation resulting in excessive influxes of glutamate and subsequent dysregulation of Ca²⁺ influx that all contribute to reduced dendrite growth and tau phosphorylation. For l-arginine/NO neurotransmission, the mechanism derives from the “protective” antiviral mechanisms of NO that correlate with pathologies such as β-amyloid peptide accumulation and functional degeneration of hippocampal neurons, respectively. More research is required to underpin the direct mechanisms that viruses might impact to induce specific pathologies.

Parkinson's disease (PD) is an age-related progressive disorder that leads to dopaminergic loss and subsequent motor dysfunction. Current therapies mainly deal with symptomatic effects, and hence, therapies targeting progressive neurodegeneration need to developed. In this study, tirzepatide, a coagonist of glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, exhibited a neuroprotective effect in preliminary studies. This study aims to evaluate the effect of tirzepatide, in comparison with exendin-4, in a rat model of PD. The effect of tirzepatide (50 and 100 nmol/kg, s.c.) and exendin-4 (8 μg/kg, s.c.) on behavioral functions, oxidative markers, inflammatory markers, dopamine level, and alpha-synuclein expression were studied against a rotenone (2 mg/kg)-induced toxicity model in rats. Tirzepatide prevented rotenone-induced motor deficits. Additionally, it significantly inhibited the rotenone-induced increase in proinflammatory cytokines TNF-α and IL-6. Furthermore, it upregulated striatal dopamine levels. It alleviated oxidative stress and alpha-synuclein aggregation. Both doses of tirzepatide exert neuroprotective effects in a PD rat model. Furthermore, the effect is dose-dependent, and a 100 nmol/kg dose of tirzepatide was found to be more effective.

Alzheimer's disease (AD), the leading cause of dementia, affects 1 in 9 people aged 65 and older. The disease impacts patients on multiple levels, from memory and problem-solving issues to difficulties with basic functions and personality changes. Unfortunately, there is only a handful of FDA-approved drugs, and none of them offer an effective cure. Therefore, recent strategies have focused on preventing and delaying disease onset, rather than curing already developed pathological changes in the brain. In this study, we investigated the therapeutic potential of carnosine (CAR), a naturally occurring dipeptide known for its multimodal mechanism of action, such as the ability to mitigate neuroinflammation, oxidative stress, and deficiencies in neurotropic factors, all of which are connected with aging-related cognitive decline and an increased risk of developing dementia. For this purpose, we utilized an okadaic acid-induced zebrafish model of AD, which replicates some of the key features of the disease, including hyperphosphorylation of tau protein, changes in Aβ-fragments, and cognitive decline. By employing a latent learning behavioral assay and fast-scan cyclic voltammetry, we evaluated the effect of CAR on the prevention of cognitive decline and neurochemical changes in the AD-like zebrafish brain. Our findings revealed that CAR prevents impaired learning and motor dysfunction in a sex-dependent manner and reduces anxiety-like behavior. Additionally, we found that CAR inhibits dopamine release impairment. Hence, our study demonstrates the potential of CAR as a promising candidate for further investigations focused on identifying molecules that could potentially serve as therapeutics for delaying the onset of AD.

Ischemic stroke remains a leading cause of morbidity and mortality worldwide, and early diagnosis is critical for improving clinical outcomes. This paper presents an optical design framework combining speckle contrast optical spectroscopy (SCOS) with multiwavelength reflectance spectroscopy to monitor subtle changes in cerebral blood flow during ischemic events. The research aims to enable precise tissue interrogation using high-resolution, low-scatter imaging. Key to the system's accuracy is a 1.55 μm small beam waist, a grating density of 1300 grooves/mm, and a 15.53 μm depth of focus. The calculated effective focal length of 8333.33 μm enhances the resolution to 4.07 μm, improving the detection of minor changes in tissue optical properties. We investigate the sensitivity of various near-infrared wavelengths (660, 785, 800, and 976 nm) to ischemic-induced changes, with particular emphasis on the 976 nm wavelength, which demonstrates superior tissue penetration and increased sensitivity to variations in blood perfusion and tissue density during ischemia. Optical markers such as spot-size widening, spatial intensity shifts, and central intensity decrease are identified as reliable indicators of ischemia. Our findings suggest that multiwavelength reflectance analysis, particularly in the near-infrared range, provides a practical, noninvasive approach for continuously monitoring ischemic strokes. This technique indicates potential for improving early diagnosis and real-time monitoring of cerebral perfusion, which allows for continuous, noninvasive monitoring of cerebral perfusion and management of ischemic strokes, improving patient outcomes and clinical decision-making.

Bri2 BRICHOS, a folded domain of the transmembrane protein Bri2 expressed in both the brain and pancreas, is an experimentally known substoichiometric inhibitor of amyloid aggregation. The molecular chaperone effectively delays fibrillization at low molar ratios for both β-amyloid (Aβ) in Alzheimer’s disease (AD) and islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). While discovering effective antiamyloid inhibitors that work at low doses is an appealing strategy to mitigate amyloid toxicity, the molecular mechanism underlying the broad and efficient antiamyloid activity of Bri2 BRICHOS remains unknown. Here, we computationally demonstrated that Bri2 BRICHOS exhibits a stronger binding affinity to fibril seeds than to monomers using atomistic discrete molecular dynamic simulations. By competing with monomers to bind the active elongation sites on newly nucleated, weakly populated fibril seeds, a small amount of Bri2 BRICHOS could block rapid fibril growth via monomer addition. The experimentally observed differential inhibition efficiency against IAPP and Aβ aggregation was found to depend on the relative fibril-binding affinities of the inhibitor compared to those of self-seeding monomers. Our computationally derived determinants for substoichiometric inhibition against amyloid aggregation by Bri2 BRICHOS may inform the future design of potent antiamyloid therapies for AD, T2D, and other amyloid diseases.

It has been reported that nicotine affects brain dopamine homeostasis. By binding to nicotinic acetylcholine receptors, including those expressed by dopaminergic neurons of the ventral tegmental area, nicotine stimulates dopamine release and signaling. Dopamine is taken up from the synaptic cleft by the dopamine transporter (DAT) into presynaptic neurons, where it is degraded by monoamine oxidase (MAO). Besides nicotine, other tobacco compounds play a role in dopamine modulation. To better understand the biological effects of nicotine and other tobacco compounds on dopamine regulation, we selected a group of tobacco compounds based on their potential affinity to bind human MAO-A and MAO-B enzymes using an in silico approach. Subsequently, we tested the putative compounds in an enzymatic assay to verify their ability to inhibit human MAO-A or MAO-B. The positive hits were harman, norharman, harmaline, and 1-ethyl-β-carboline. While harman and norharman have been extensively studied, both harmaline and 1-ethyl-β-carboline have not been described in the context of tobacco and MAO inhibition before. We investigated DAT activity in an overexpressing cell line and dopamine release and uptake in rat striatal synaptosomes. We clearly demonstrate that tested MAO-A inhibitors (MAO-AIs) significantly attenuated human DAT activity and consequent dopamine uptake, establishing a functional connection between MAOIs and dopamine uptake via DAT. Interestingly, the tested MAO-AIs elicited pronounced dopamine release in crude synaptosomal preparations. In summary, this in vitro study demonstrates that tested MAO-AIs found in cigarette smoke not only reduce MAO activity but also strongly impact dopamine homeostatic mechanisms via DAT. Further in vivo investigations would advance our understanding of the underlying mechanisms of dopamine regulation and homeostasis.

Voltage-gated sodium channels are the main targets of antiepileptic drugs, such as sodium valproate (VPA). Single nucleotide polymorphisms (SNPs) in the Nav1.6 isoform (SCN8A) have been reported to be closely associated with motor dysfunction in pediatric akathisia epileptica. In this study, we conducted a genetic screening of pediatric patients with seizures treated solely with VPA and identified two novel missense mutations of SCN8A (A1534V and Q1853H). Electrophysiological results revealed that the peak currents of the A1534V variant were smaller compared to that of the wild-type (WT) channel. The A1534V variant also caused a positive shift in the I–V curve, indicating a change in the voltage dependence of activation compared to the WT channels. In contrast, VPA induced a significant negative shift in the inactivation of both WT and A1534V mutant. However, the inhibition of currents by VPA was weaker in the A1534V variant than in WT. Furthermore, the recovery time constant of the A1534V variant was shorter than that of WT when treated with VPA. Regrettably, although the Q1853H variant can be expressed in HEK293T cells, the detected current is too small (approximately 50 pA). In conclusion, our results suggest that the A1534V mutation is a novel loss-of-function variant that exhibits moderate insensitivity to VPA. These results underscore the importance of Nav1.6 as a key target in epilepsy and highlight the necessity of analyzing its role in the pathological process.

The nectin family of cell adhesion molecules (CAMs) comprising nectins and nectin-like molecules has emerged as a key regulator of various pivotal neural processes, including neuronal development, migration, synapse formation, and plasticity. Nectins engage in homophilic and heterophilic interactions to mediate cell–cell adhesion, contributing to the establishment and maintenance of neural circuits. Their extracellular domains facilitate trans-synaptic interactions, while intracellular domains participate in signaling cascades influencing cytoskeletal dynamics and synaptic function. The exhibition of distinct localization patterns in neurons, astrocytes, and the blood–brain barrier underscores their diverse roles in the brain. The dysregulation of nectins has been implicated in several neurological disorders, such as neurodevelopmental disorders, depression, schizophrenia, and Alzheimer’s disease. This review examines the structural and functional characteristics of nectins and their distribution and molecular mechanisms governing neural connectivity and cognition. It further discusses experimental studies unraveling nectin-mediated pathophysiology and potential therapeutic interventions targeting nectin-related pathways. Collectively, this comprehensive analysis highlights the significance of nectins in brain development, function, and disorders, paving the way for future research directions and clinical implications.

The ApoE4 allele of apolipoprotein E (ApoE4) is the strongest hereditary predisposition to Alzheimer’s disease, even though ApoE4 only differs from the more common ApoE3 by a single amino acid substitution. Previous studies have shown that ApoE4 is more susceptible to proteolytic degradation than ApoE3. This is an important finding because of ApoE’s role in cholesterol homeostasis and lipid transport in the brain. The molecular determinants of the increased susceptibility of ApoE4 to proteolysis are unknown. Here, we apply a combination of spectrometric and spectroscopic methods to show that amyloid-β (Aβ) peptides, including Aβ(1–40) and Aβ(pyroE3–42), differentially modulate the plasmin-dependent degradation of ApoE3 and ApoE4. In particular, our data reveal that while the Aβ peptides do not affect the proteolysis of ApoE3, the peptides enhance the degradation of ApoE4 significantly. Overall, this work motivates therapeutic development that targets the Aβ-induced dysregulation of ApoE4 homeostasis in individuals carrying the ApoE4 allele.