Journal of Neurochemistry最新文献

Neuroinflammatory conditions linked to iron dysregulation pose significant challenges in neurodegenerative diseases. Iron-loaded microglia are observed in the brains of patients with various neuroinflammatory conditions, yet how iron overload affects microglial function and contributes to various neuroinflammatory processes is poorly understood. This in vitro study elucidates the relationship between excess iron, cofilin activation, and microglial function, shedding light on potential therapeutic avenues. Iron overload was induced in Human Microglial Clone 3 cells using ferrous sulfate, and the expressions of ferritin heavy chain, ferritin light chain, divalent metal transporter 1, cofilin, p-cofilin, nuclear factor-κB (NF-κB), and various inflammatory cytokines were analyzed using real-time quantitative polymerase chain reaction, immunocytochemistry, Western blotting, and enzyme-linked immunosorbent assay. Results revealed a notable increase in cofilin, NF-κB, and inflammatory cytokine expression levels following excess iron exposure. Moreover, treatment with deferoxamine (DFX), a known iron chelator, and a novel cofilin inhibitor (CI) synthesized in our laboratory demonstrate a mitigating effect on iron-induced cofilin expression. Furthermore, both DFX and CI exhibit promising outcomes in mitigating the inflammatory consequences of excess iron, including the expression of pro-inflammatory cytokines and NF-κB activation. These findings suggest that both DFX and CI can potentially alleviate microglia-induced neuroinflammation by targeting both iron dysregulation and cofilin-mediated pathways. Overall, this study provides valuable insights into iron-induced cofilin activation and microglial activation, offering avenues for potential targeted therapies for neuroinflammatory conditions associated with iron and cofilin dysregulation in neurodegenerative diseases.

From the day we are born, the nervous system is subject to insult, disease and degeneration. Aberrant phosphorylation states in neurofilaments, the major intermediate filaments of the neuronal cytoskeleton, accompany and mediate many pathological processes in degenerative disease. Neuronal damage, degeneration and death can release these internal components to the extracellular space and eventually the cerebrospinal fluid and blood. Sophisticated assay techniques are increasingly able to detect their presence and phosphorylation states at very low levels, increasing their utility as biomarkers and providing insights and differential diagnosis for the earliest stages of disease. Although a variety of studies focus on single or small clusters of neurofilament phosphorylated epitopes, this review offers a wider perspective of the phosphorylation landscape of the neurofilament heavy subunit, a major intermediate filament component in both ageing and disease.

Stressful life events and glucocorticoid (stress) hormones appear to increase the risk of Alzheimer's disease and hasten its progression, but the reasons for this remain unclear. One potential explanation is that when amyloid β (Aβ) pathology is accumulating in the preclinical disease stage, glucocorticoid receptor signalling during stressful events exacerbates cellular dysfunction caused by Aβ. Alternatively, Aβ may disrupt glucocorticoid receptor signalling. To explore these possibilities, we investigated whether the synthetic glucocorticoid dexamethasone and Aβ have overlapping effects on the cellular proteome and whether Aβ influences canonical glucocorticoid receptor function. Human olfactory neurosphere-derived (ONS) cells, collected from the olfactory mucosa of six adult donors, were treated with soluble Aβ40 or Aβ42 followed by dexamethasone. Proteins were quantified by mass spectrometry. After 32 h treatment, Aβ40 and Aβ42 both induced profound changes in innate immunity-related proteins. After 72 h, Aβ42 formed widespread aggregates and induced few proteomic changes, whereas Aβ40 remained soluble and altered expression of mitochondrial and innate immunity-related proteins. ONS cells revealed overlapping impacts of Aβ40 and dexamethasone, with 23 proteins altered by both treatments. For 16 proteins (including eight mitochondrial proteins) dexamethasone counteracted the effects of Aβ40. For example, caspase 4 and methylmalonate-semialdehyde dehydrogenase were increased by Aβ40 and decreased by dexamethasone. Consistent with this finding, Aβ40 increased, but dexamethasone decreased, ONS cell proliferation. For seven proteins, including superoxide dismutase [Mn] mitochondrial, dexamethasone exacerbated the effects of Aβ40. For some proteins, including complement C3, the effects of dexamethasone differed depending on whether Aβ40 was present or absent. Neither Aβ species influenced glucocorticoid receptor nuclear translocation. Overall, this study revealed that glucocorticoid receptor signalling modifies the intracellular effects of Aß40, counteracting some effects and exacerbating others. It suggests that cellular mechanisms through which glucocorticoid receptor signalling influences Alzheimer's disease risk/progression are complex and determined by the balance of beneficial and detrimental glucocorticoid effects.

Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.

Parkinson's disease (PD) is the second-fastest growing neurodegenerative disease in the world. The major clinical symptoms rigor, tremor, and bradykinesia derive from the degeneration of the nigrostriatal pathway. However, PD is a multi-system disease, and neurodegeneration extends beyond the degradation of the dopaminergic pathway. Symptoms such as postural instability, freezing of gait, falls, and cognitive decline are predominantly caused by alterations of transmitter systems outside the classical dopaminergic axis. While levodopa and deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus effectively address PD primary motor symptoms, they often fall short in mitigating axial symptoms and cognitive impairment. Along these lines, the cholinergic system is increasingly recognized to play a crucial role in governing locomotion, postural stability, and cognitive function. Thus, there is a growing interest in bolstering the cholinergic tone by DBS of cholinergic targets such as the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NBM), aiming to alleviate these debilitating symptoms resistant to traditional treatment strategies targeting the dopaminergic network. This review offers a comprehensive overview of the role of cholinergic dysfunction in PD. We discuss the impact of PPN and NBM DBS on the management of symptoms not readily accessible to established DBS targets and pharmacotherapy in PD and seek to provide guidance on patient selection, surgical approach, and stimulation paradigms.

Extra-cerebral manifestations of Alzheimer's disease (AD) develop in the retina, which is, therefore, considered a "window to the brain". Recent studies demonstrated the dysregulation of the endocannabinoid (eCB) system (ECS) in AD brain. Here, we explored the possible alterations of ECS and the onset of gliosis in the retina of AD-like mice. Tg2576 (TG) mice overexpressing the amyloid precursor protein (APP) were used at the age of 12 months, when hippocampal β-amyloid plaques had not been developed yet. Analysis of retinal gliosis showed a significant increase in the number of IBA1 (+) microglia cells in TG versus wild type (WT). Gliosis was not associated with retinal β-amyloid plaques, evident retinal degenerative signatures, or excitotoxicity; instead, oxidative stress burden was observed as increased acrolein levels. Analysis of the ECS (receptors/metabolic enzymes) through western blotting (WB) revealed the up-regulation of cannabinoid receptor 2 (CB₂) and monoacylglycerol lipase (MAGL), the enzyme responsible for the degradation of 2-arachidonoylglycerol (2-AG), in TG retinas. Fluorescence intensity analysis of anti-CB₂ and anti-MAGL immuno-stained cryosections was consistent with WB, showing their up-regulation throughout the retinal layers. No statistically significant differences were found for the other enzymes/receptors of the ECS under study. However, linear regression analysis for individual animals showed a significant correlation between CB₂ and fatty acid amide hydrolase (FAAH), diacylglycerol lipase α/β (DAGLα/β), and APP; instead, a significant negative correlation was found between MAGL and APP. Finally, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) demonstrated a significant reduction of 2-AG in TG retinas (~0.34 ng/mg) compared to WT (~1.70 ng/mg), while a trend toward increase was found for the other eCB anandamide (AEA). Overall, our data indicate that gliosis and ECS dysregulation-in particular of CB₂, MAGL and 2-AG-occur in the retina of AD-like mice before retinal degeneration and development of hippocampal β-amyloid plaques.

Vascular dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). While sodium is essential for maintaining vascular function, its role in AD pathology remains unclear. We included 353 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), assessing serum sodium levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), and cognitive function. An independent sample (N = 471) with available CSF sodium-related proteins and AD biomarkers was also included. Associations between serum sodium levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Spearman's correlation analyses assessed the relationships between CSF sodium-related proteins and AD biomarkers. Higher serum sodium levels were associated with increased AD pathology, reduced hippocampal volume, and greater cognitive decline (all p < 0.05). The relationship between serum sodium and amyloid PET was evident in several AD-susceptible brain regions, including the neocortex and limbic system. Individuals with high serum sodium exhibited higher tau pathology, lower hippocampal volume, and more severe cognitive decline per unit increase in amyloid PET compared to those with low serum sodium (all p < 0.05). Among the 14 CSF sodium-related proteins, which were inter-correlated, six were significantly correlated with CSF AD pathology and amyloid PET, while two were correlated with hippocampal volume and cognitive function, with sodium channel subunit beta-2 (SCN2B) and sodium channel subunit beta-3 (SCN3B) showing the strongest correlations. These findings underscore the crucial role of serum sodium in AD progression, highlighting a potential network of sodium dysregulation involved in AD pathology. Targeting sodium may offer a novel therapeutic approach to slowing AD progression, particularly by impeding the progression of amyloid-related downstream events.

Acetylcholinesterase (AChE) has functions in neuroinflammation, beyond its classical role in neurotransmission. Understanding the role of AChE in neuroinflammation is of great significance, as it highlights the potential therapeutic targets for the treatment of neurodegenerative diseases. In an in vitro study, the expression of AChE was up-regulated in lipopolysaccharide (LPS)-induced microglia/macrophage and contrarily potentiated the inflammatory responses via disturbing the cholinergic anti-inflammatory pathway (CAP). However, the regulation of AChE in neuroinflammation has not been revealed in vivo yet. Here, we aim to uncover the inflammatory roles of microglial AChE in LPS-induced neuroinflammation by using the conditional AChE over-expression mouse model. AChE was specifically over-expressed in the myeloid cell linkage of mouse by applying CRISPR/cas9 combined with Cre-LoxP system. LPS was intraperitoneally injected into the mice to induce inflammation. The results showed that the inflammation, induced by LPS, was aggravated in the brain of transgenic mice having over-expression of AChE in microglia. The expressions of pro-inflammatory cytokines were robustly up-regulated in the brains of LPS-treated transgenic mice, as compared to the LPS-treated wildtypes. In parallel, the activations of microglia and astrocytes in hippocampus were enhanced significantly in AChE transgenic mice. Transcriptomics analysis further confirmed the severer inflammation in the transgenic mice than the wildtype after LPS administration. These findings shed light on the regulation of microglial AChE in neuroinflammation in vivo for the first time, presenting another angle to understand the role of AChE in neurodegenerative diseases.

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post-prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome-wide significant (p < 5E-08, primary analyses) and 61 suggestive (p < 1E-05, secondary analyses) ISI genetic variants from large-scale genome-wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta-analysis to combine MR estimates from two non-overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68-0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82-0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR-associated T2D and AD.

Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ load. In addition, the P-tau181-linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ- and CN Aβ+ individuals. Significant positive associations of medium- and long-chain acylcarnitines (ACs) were observed with P-tau181 in the entire cohort, CN Aβ- and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation-mediated energy metabolism pathways. However, in CN Aβ-, additional linear associations of P-tau181 were observed with muscle metabolism and nitric oxide homeostasis-associated metabolites. Upon investigating the P-tau181-linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium- and long-chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET-Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET-Aβ status in older adults. Therefore, plasma P-tau181-linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross-sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings.