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Bushen Tiansui decoction is composed of six traditional Chinese medicines: Herba Epimedii, Radix Polygoni multiflori, Plastrum testudinis, Fossilia Ossis Mastodi, Radix Polygalae, and Rhizoma Acorus tatarinowii. Because Bushen Tiansui decoction is effective against amyloid beta (Aβ) toxicity, we hypothesized that it would reduce hippocampal synaptic damage and improve cognitive function in Alzheimer's disease. To test this hypothesis, we used a previously established animal model of Alzheimer's disease, that is, microinjection of aggregated Aβ25-35 into the bilateral brain ventricles of Sprague-Dawley rats. We found that long-term (28 days) oral administration of Bushen Tiansui decoction (0.563, 1.688, and 3.375 g/mL; 4 mL/day) prevented synaptic loss in the hippocampus and increased the expression levels of synaptic proteins, including postsynaptic density protein 95, the N-methyl-D-aspartate receptor 2B subunit, and Shank1. These results suggested that Bushen Tiansui decoction can protect synapses by maintaining the expression of these synaptic proteins. Bushen Tiansui decoction also ameliorated measures reflecting spatial learning and memory deficits that were observed in the Morris water maze (i.e., increased the number of platform crossings and the amount of time spent in the target quadrant and decreased escape latency) following intraventricular injections of aggregated Aβ25-35 compared with those measures in untreated Aβ25-35-injected rats. Overall, these results provided evidence that further studies on the prevention and treatment of dementia with this traditional Chinese medicine are warranted.

During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities and impairments collectively referred to as neurodevelopmental disorders. Cell adhesion molecules (CAMs), present on the cell surface, take part in the neurodevelopmental process regulating migration and recognition of specific cells to form functional neuronal assemblies. Among CAMs, the members of the protocadherin (PCDH) group stand out because they are involved in cell adhesion, neurite initiation and outgrowth, axon pathfinding and fasciculation, and synapse formation and stabilization. Given the critical role of these macromolecules in the major neurodevelopmental processes, it is not surprising that clinical and basic research in the past two decades has identified several PCDH genes as responsible for a large fraction of neurodevelopmental disorders. In the present article, we review these findings with a focus on the non-clustered PCDH sub-group, discussing the proteins implicated in the main neurodevelopmental disorders.

To explore the pathophysiological mechanisms of antiseizure and adverse behavioural/psychiatric effects of brivaracetam and levetiracetam, in the present study, we determined the effects of brivaracetam and levetiracetam on astroglial L-glutamate release induced by artificial high-frequency oscillation (HFO) bursts using ultra-high-performance liquid chromatography. Additionally, the effects of brivaracetam and levetiracetam on protein expressions of connexin43 (Cx43) and synaptic vesicle protein 2A (SV2A) in the plasma membrane of primary cultured rat astrocytes were determined using a capillary immunoblotting system. Acutely artificial fast-ripple HFO (500 Hz) burst stimulation use-dependently increased L-glutamate release through Cx43-containing hemichannels without affecting the expression of Cx43 or SV2A in the plasma membrane, whereas acute physiological ripple HFO (200 Hz) stimulation did not affect astroglial L-glutamate release or expression of Cx43 or SV2A. Contrarily, subchronic ripple HFO and acute pathological fast-ripple HFO (500 Hz) stimulations use-dependently increased L-glutamate release through Cx43-containing hemichannels and Cx43 expression in the plasma membrane. Subchronic fast-ripple HFO-evoked stimulation produced ectopic expression of SV2A in the plasma membrane, but subchronic ripple HFO stimulation did not generate ectopic SV2A. Subchronic administration of brivaracetam and levetiracetam concentration-dependently suppressed fast-ripple HFO-induced astroglial L-glutamate release and expression of Cx43 and SV2A in the plasma membrane. In contrast, subchronic ripple HFO-evoked stimulation induced astroglial L-glutamate release, and Cx43 expression in the plasma membrane was inhibited by subchronic levetiracetam administration, but was not affected by brivaracetam. These results suggest that brivaracetam and levetiracetam inhibit epileptogenic fast-ripple HFO-induced activated astroglial transmission associated with hemichannels. In contrast, the inhibitory effect of therapeutic-relevant concentrations of levetiracetam on physiological ripple HFO-induced astroglial responses probably contributes to the adverse behavioural/psychiatric effects of levetiracetam.

The efficient and prolonged neurotransmission is reliant on the coordinated action of numerous synaptic proteins in the presynaptic compartment that remodels synaptic vesicles for neurotransmitter packaging and facilitates their exocytosis. Once a cycle of neurotransmission is completed, membranes and associated proteins are endocytosed into the cytoplasm for recycling or degradation. Both exocytosis and endocytosis are closely regulated in a timely and spatially constrained manner. Recent research demonstrated the impact of dysfunctional synaptic vesicle retrieval in causing retrograde degeneration of midbrain neurons and has highlighted the importance of such endocytic proteins, including auxilin, synaptojanin1 (SJ1), and endophilin A (EndoA) in neurodegenerative diseases. Additionally, the role of other associated proteins, including leucine-rich repeat kinase 2 (LRRK2), adaptor proteins, and retromer proteins, is being investigated for their roles in regulating synaptic vesicle recycling. Research suggests that the degradation of defective vesicles via presynaptic autophagy, followed by their recycling, not only revitalizes them in the active zone but also contributes to strengthening synaptic plasticity. The presynaptic autophagy rejuvenating terminals and maintaining neuroplasticity is unique in autophagosome formation. It involves several synaptic proteins to support autophagosome construction in tiny compartments and their retrograde trafficking toward the cell bodies. Despite having a comprehensive understanding of ATG proteins in autophagy, we still lack a framework to explain how autophagy is triggered and potentiated in compact presynaptic compartments. Here, we reviewed synaptic proteins’ involvement in forming presynaptic autophagosomes and in retrograde trafficking of terminal cargos. The review also discusses the status of endocytic proteins and endocytosis-regulating proteins in neurodegenerative diseases and strategies to combat neurodegeneration.

Background: The protective Icelandic mutation in the amyloid precursor protein (APP) gene, APPA673T, identified in Icelandic and other Nordic populations is associated with a significantly lower risk of developing Alzheimer’s disease (AD). Conflicting results have been reported for the human APPA673T mutation in various knock-in models of AD, but the effect of the mouse APPA673T form in 5× familial AD (5×FAD) mice has never been investigated. Methods: We crossed C57Bl6/J mice expressing a single point mutation edited into the murine APP gene via Clustered Regularly Interspaced Short Palindromic Repeats–CRISPR-associated (CRISPR-Cas) gene editing, termed mAPPA673T, with 5×FAD mice that overexpress human APP carrying the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations as well as human presenilin-1 (PS1) with two mutations (M146L and L286V); the resulting mice were termed 5×FAD × mAPPA673T mice. We investigated amyloid beta-protein (Aβ) pathology in 5×FAD × mAPPA673T, 5×FAD and their respective controls, mAPPA673T, and C57Bl6/J wild type mice, at 6-months of age using immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (ELISA). Results: We found a moderate yet significant reduction in Aβ plaque size in male 5×FAD × mAPPA673T compared with 5×FAD mice. No differences were observed for soluble/insoluble Aβ40 and Aβ42 levels per se, but lower plaque count/area was found in 5×FAD × mAPPA673T mice when Aβ42/Aβ40 ratios were low, suggesting a genotype-dependent sensitivity to Aβ aggregation and accumulation. Conclusions: The mAPPA673T mutation has the potential to modify Aβ pathology in 5×FAD mice at the age of 6 months.

A loss of synaptic density and connectivity is observed in multiple brain regions of Alzheimer’s disease (AD) patients, resulting in a reduced expression of synaptic proteins such as SNAP-25 (synaptosomal-associated-protein-25). SNAP-25 alterations thus could be an index of the degree of synaptic degeneration in the central nervous system (CNS). We isolated from serum of both AD patients and healthy controls (HC) a population of neuron-derived exosomes (NDEs) and measured the concentrations of SNAP-25 contained in such NDEs. The levels of SNAP-25 carried by NDEs were reduced in AD patients (mean 459.05 ng/ml, SD 146.35 ng/ml) compared to HC (mean 686.42 ng/ml, SD 204.08 ng/ml) ( p  < 0.001). As a further confirmation of these results, ROC (receiver operating characteristic) analyses indicated that the level of SNAP-25 carried by NDEs has the power to discriminate between AD and HC (AUC = 0.826, sensitivity = 87.5%, specificity = 70.6%, p  < 0.0001, cut-off value 587.07 ng/ml). Notably, a correlation between the levels of SNAP-25 carried by NDEs and levels and cognitive status measured by MMSE score ( r  = 0.465, 95% CI 0.11 to 0.714, p  = 0.01) was detected. This is the first report of SNAP-25 measurement in serum. These data suggest that NDE-carried SNAP-25 could be an effective and accessible biomarker that reflects synapses integrity in the brain.

Presynaptic Ca2+ entry occurs through voltage-gated Ca2+ (CaV) channels which are activated by membrane depolarization. Depolarization accompanies neuronal firing and elevation of Ca2+ triggers neurotransmitter release from synaptic vesicles. For synchronization of efficient neurotransmitter release, synaptic vesicles are targeted by presynaptic Ca2+ channels forming a large signaling complex in the active zone. The presynaptic CaV2 channel gene family (comprising CaV2.1, CaV2.2, and CaV2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are responsible for channel modulation by interacting with regulatory proteins. This article overviews modulation of the activity of CaV2.1 and CaV2.2 channels in the control of synaptic strength and presynaptic plasticity.

Sevoflurane anesthesia is widely used in pediatric patients. Clinical studies report memory impairment in those exposed to general anesthesia early in life. DNA methylation is essential for the modulation of synaptic plasticity through regulating the transcription of synaptic genes. Therefore, we tested whether neonatal sevoflurane exposure affects learning and memory underlying the hippocampal DNA methylation of synaptic genes. Male Sprague-Dawley rats were exposed to 3% sevoflurane or air for 2 h daily from postnatal day 7 (P7) to P9. 5-aza-2-deoxycytidine (5-AZA), an inhibitor of DNA methyltransferases (DNMTs), was intraperitoneally injected 30 min before sevoflurane or air exposure on P7–9. The rats were euthanized 6, 12, 24 h, and 28 days after the last sevoflurane exposure, followed by the determination of global and gene-specific DNA methylation. The expression of synaptic proteins and synaptic density and the transcription of Dnmts and ten eleven translocations (Tets) in the hippocampus were measured. The ability of learning and memory was assessed using Morris water maze, novel object recognition, and intruder tests. Repeated neonatal sevoflurane exposure impaired cognitive, social, and spatial memory. The memory impairment was associated with the increased Dnmt1, Dnmt3a, and 5-methylcytosine level and the decreased Tet1 and 5-hydromethylcytosine level. Sevoflurane subsequently induced hypermethylation of Shank2 , Psd95 , Syn1 , and Syp gene and down-regulated the expression of synaptic proteins, which finally led to the decrease of synaptic density in a time-dependent manner. Notably, 5-AZA pretreatment ameliorated learning and memory in sevoflurane-treated rats. In conclusion, neonatal exposure to sevoflurane can impair learning and memory through DNA methylation of synaptic genes.

[This corrects the article DOI: 10.3389/fphar.2023.1122541.].

Diabetes mellitus is metabolic syndrome and a risk factor for cognitive dysfunction-related diseases such as dementia, especially Alzheimer’s disease (AD), which is associated with chronic inflammation and abnormal insulin signaling pathway. Exercise, a known potential therapy for diabetes, can also alleviate neurodegeneration. We evaluated the effects of aerobic exercise on inflammation and insulin signaling pathway in the prefrontal cortex of diabetic rats. Male SD rats were fed with a normal diet or a high-fat diet (HFD) for 8 weeks. Then, part of the HFD rats was selected for aerobic exercise training. Our results show that aerobic exercise can improve the expression of synaptic plasticity-related proteins and reduce the phosphorylation of Tau by inhibiting the inflammatory signaling pathway and ameliorating the insulin signaling pathway in diabetic rats.