NeuroMolecular Medicine最新文献

Chronic cerebral hypoperfusion (CCH) is a key pathological hallmark observable in multiple subtypes of cerebral small vessel disease (CSVD). This condition causes both structural and functional changes within the brain's vascular system, and is particularly damaging to brain microvascular endothelial cells (BMECs). The exact molecular mechanisms underlying BMEC impairment in CCH remain insufficiently defined despite their clinical importance. Emerging evidence indicates that disturbances in intracellular lipid metabolism might contribute substantially to promoting endothelial inflammation and functional deficits. This study aims to investigate whether aberrant lipid metabolism contributes to endothelial inflammation and tight junction (TJ) dysfunction in BMECs under the condition of CCH, and to assess the therapeutic potential of intervention with simvastatin. A rat model of chronic CSVD was created via permanent bilateral ligation of the common carotid arteries (2VO) in animal subjects. Samples of cortical microvasculature were collected at predefined intervals for transcriptome profiling. Assessments of lipid metabolism, inflammation-related factors, and TJ protein levels were conducted in both in vivo and after induction of hypoxia and administration of simvastatin. At 14d post-2VO, mRNA expression of TJ proteins including occludin (Ocln), claudin-5 (Cldn5), and zonula occludens-1 (Zo-1) was significantly downregulated in BMECs compared to sham controls. Simultaneously, there was a notable buildup of lipid droplets, rise in cholesterol levels, and upregulation of pro-inflammatory indicators including VCAM1, TNF-α, and ICAM1. Simvastatin administration effectively reduced lipid buildup, suppressed inflammation, and restored TJ integrity. Dysregulated lipid metabolism and heightened inflammatory responses contribute to TJ disruption in BMECs with CCH. Simvastatin therapy mitigates lipid accumulation, dampens inflammation, and improves TJ function in BMECs with CCH.

Neurodegenerative diseases impose a substantial and growing global burden, affecting millions worldwide and leading to high medical, social, and economic costs. These are characterized by progressive neuronal dysfunction and loss, leading to cognitive, motor, and behavioral impairments. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are driven by intertwined mechanisms of oxidative stress, neuroinflammation, protein aggregation, and neuronal apoptosis. Activation of the TLR-2/NF-κB axis promotes neuroinflammation and pyroptotic cell death through excessive production of pro-inflammatory cytokines, contributing to neuronal damage. Dysregulation of the TLR-2/Akt/mTOR pathway impairs autophagy, leading to defective clearance and accumulation of α-synuclein, a central event in synucleinopathies. Moreover, compromised Nrf2-mediated antioxidant signaling weakens cellular redox homeostasis and anti-apoptotic defenses, thereby linking redox imbalance to caspase-dependent neuronal apoptosis. Given the complex and multifactorial nature of neurodegenerative diseases, there is a pressing need for multitarget agents. Phloretin is a natural dihydrochalcone predominantly found in apples, pears, and strawberries. It exhibits broad pharmacological activities, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, making it a promising multitarget phytochemical for neurodegenerative conditions. Phloretin mediates its neuroprotective properties through the modulation of several mediators, including Aβ, TLR-2, NF-κB, COX, iNOS, PPARγ, Nrf2, beclin-1, Bax, Bcl-2, caspases, PI3K/Akt, mTOR, pro-inflammatory cytokines, and antioxidant enzymes, among others. Despite compelling preclinical evidence, critical gaps remain regarding phloretin's effects on inflammasome initiation, ER stress responses, mitophagy, neurotrophic signaling, and, importantly, its clinical safety and efficacy, underscoring the need for integrated mechanistic studies and well-designed clinical trials.

Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD) is an inherited metabolic disorder which is good responsive to riboflavin treatment. The phenotypic spectrum of adult-onset RR-MADD is highly heterogeneous. In this study, we described three patients with adult-onset RR-MADD presented with muscle weakness and spinal cord involvement. These three patients presented with adult-onset limb weakness, dyspnea, along with sensory levels changes (patient 1 below T2 level, patient 2 below T6 level, and patient 3 below T12 level, respectively). All patients displayed elevated acylcarnitine and urinary organic acids. Muscle biopsies in patient 1 and patient 2 revealed the presence of lipid vacuoles and COX-negative fibers. Genetic analysis identified ETFDH mutation (c.524G > A (p.R175H)) in patient 1, and a compound heterozygous ETFDH mutation (c.34G > C (p.A12P)/c.736G > A (p.E246K)) in patient 2. Spinal-cord MRI excluded structural lesions, whereas muscle MRI indicated fatty infiltration. Short-term riboflavin treatment proved effective in alleviating muscle weakness, while long-term administration of riboflavin, coenzyme Q10, and vitamin B12 demonstrated efficacy in alleviating spinal cord involvement. Inconclusion, our findings suggest that spinal cord involvement may manifest in certain patients with adult-onset RR-MADD, which expand the neurological spectrum of adult-onset RR-MADD.

The Presenilins are multi-pass transmembrane proteins that form part of the multi-protein gamma secretase complex. The hydrolytic activity of the gamma secretase complex is responsible for the cleavage of a wide range of substrates, including the amyloid precursor protein (APP) - a proteolytic event that is the final step in the production of the amyloid beta peptide, a protein fragment deposited in the brains of individuals with Alzheimer's disease (AD). Both PSEN1 and PSEN2, the genes encoding the Presenilins, are mutated in familial AD, generating intense interest in the activity and function of these proteins. Despite this attention, the post-translational modification and regulation of the Presenilins is poorly understood. In order to address this gap in our knowledge, a bioinformatic approach was taken to examine the extant evidence for Presenilin phosphorylation. Derived from the Phosphosite repository, these data reveal divergent patterns of phosphorylation across Presenilin 1 and 2, highlighting distinct regulatory pathways that have implications for our understanding of the biology of these proteins, gamma secretase, and drug discovery targeting this complex.

Neuronal differentiation into specific subtypes is crucial for nervous system development and function, guided by neurotrophic factors. γ-Enolase, a neuron-specific glycolytic enzyme, exhibits neurotrophic-like properties and supports neuronal differentiation; however, its role in specific neuronal subtypes remains unknown. Here, we investigate the role of γ-enolase in differentiation dopaminergic-, cholinergic-, and adrenergic-like neuronal cells. Our results demonstrate that γ-enolase expression is significantly upregulated in differentiated cells, with the highest expression observed in cholinergic-like neurons. Full-length γ-enolase, compared to its truncated form, promoted enhanced neurite outgrowth and increased β-tubulin, a cytoskeletal marker. Conversely, silencing endogenous γ-enolase significantly reduced neurite length, confirming its essential role in driving neuronal morphological maturation. Furthermore, a γ-enolase-derived peptide corresponding to the active C-terminus of γ-enolase significantly promoted neurite outgrowth and increased β-tubulin expression, particularly in cholinergic-like neuronal cells. Notably, γ-enolase activity is regulated by cathepsin X, a lysosomal peptidase that cleaves γ-enolase at its C-terminus, reducing its neurotrophic effects. Confocal microscopy revealed increased co-localization of γ-enolase and cathepsin X in differentiated neuronal cells, emphasizing their interaction in cholinergic-like neurons. Inhibiting cathepsin X preserved active γ-enolase, promoted neuronal differentiation, and altered cytoskeletal marker expression. These findings suggest an important role for γ-enolase in cholinergic-like neuronal cells and propose cathepsin X as a regulatory modulator of γ-enolase activity, suggesting novel therapeutic strategies for neuroregeneration.

Chronic neuroinflammation is recognized as a pivotal mechanism responsible for secondary damage following mild traumatic brain injury (mTBI), underscoring the critical need for therapeutic strategies capable of mitigating this pathological process. This study evaluated the anti-inflammatory properties of stearidonic acid ethanolamide (SDEA, C20H33NO2). The findings indicate that mTBI triggers persistent neuroinflammation, which is correlated with cognitive deficits. A ten-day treatment regimen with SDEA at 10 mg/kg/day facilitated the restoration of cognitive abilities and suppressed the neuroinflammatory cascade in a mouse model. Memory impairments and anxiety-like behaviors were quantified through behavioral testing. Immunohistochemical techniques were employed to examine alterations in Iba-1-positive microglia and nNOS-positive cells within the cortical and hippocampal regions (CA1 and DG). The expression profiles of pro- and anti-inflammatory markers (IL1β, IL6, TNFα, CD68, CD206) were analyzed via reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Furthermore, an in vitro model of LPS-induced inflammation in SIM-A9 microglial cells was utilized to investigate the impact of SDEA on the production of cytokines, reactive oxygen species (ROS), nitric oxide (NO), and nitrites. Integrative analysis of in vivo and in vitro data showed that SDEA: (1) improved behavioral deficits by reducing anxiety and improving working memory; (2) suppressed pro-inflammatory microglial activation and nNOS-positive cells; (3) lowered pro-inflammatory cytokine, ROS, NO, and nitrite concentrations; and (4) enhanced CD206 marker expression in the cerebral cortex. These collective findings underscore the therapeutic potential of SDEA for traumatic CNS injuries.

Lactylation has been identified as a novel epigenetic modification involved in neuroinflammation, mitochondrial dysfunction, and tau pathology. Although its relevance has been suggested in Alzheimer's disease (AD), its causal contribution to distinct dementia subtypes remains unclear. We conducted a two-sample Mendelian randomization (MR) study to investigate whether the genetically predicted expression of 15 lactylation-related genes is causally associated with the risk of five dementia subtypes: Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). Gene expression instruments were selected from whole-blood eQTL data (n = 31,684), and outcome data were derived from large-scale GWASs. The inverse-variance weighted (IVW) method served as the primary analytical approach, with Bonferroni correction (α = 0.05/15) applied for multiple testing. After correction, six gene-dementia associations remained statistically significant. Increased expression of EP300 and PFKP was associated with higher AD risk, while SIRT1 and LDHC showed protective effects against PDD. NUP50 was associated with increased FTD risk, and STMN1 with reduced risk of DLB. No significant associations were detected for VaD. All findings were robust in sensitivity analyses and supported by brain expression evidence from GTEx. Genetic evidence was provided for a causal relationship between lactylation-related gene expression and dementia subtype risk, offering potential mechanistic insights and therapeutic targets.

Alzheimer's disease is a multifaceted neurodegenerative condition marked by the build-up of amyloid plaques and neurofibrillary tangles that lead to progressive cognitive impairment. Neuroinflammation, especially the activation of microglia, plays a pivotal part in driving this pathology. Microglia are the brain's resident immune cells and can adopt a spectrum of activation states that support either neuroprotection or neurodegeneration. Evidence shows that their phenotypes are highly dynamic and shaped by environmental influences and pathological signals. During the early phases of the disease, microglia tend to assume anti-inflammatory roles that facilitate plaque clearance and promote tissue recovery. Prolonged or dysregulated activation, however, shifts them toward a pro-inflammatory state that amplifies neuronal damage. Several molecular pathways including JAK STAT, PI3K AKT, and MAPK are central to regulating these processes and have emerged as promising therapeutic targets. This review summarizes current insights into microglial phenotypic transitions, the signaling mechanisms governing their activation, and the therapeutic potential of modulating neuroinflammation. Enhancing the neuroprotective capacity of microglia, suppressing chronic inflammatory responses, and targeting key receptors such as TREM2 and P2 × 7 represent potential strategies. A deeper understanding of microglial interactions with other glial cells and the molecular drivers of their activation may provide new avenues for slowing or halting the progression of Alzheimer's disease and related neurodegenerative disorders.