The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier’s integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.
The repeated failures of anti-amyloid therapies in Alzheimer’s disease (AD) have exposed critical limitations of the linear amyloid cascade hypothesis and underscored the need for a broader etiological framework. The objective of this review is to synthesise mechanistic evidence for an exposome‑based model of sporadic AD that integrates metabolic, inflammatory, and sleep/circadian contributions to brain aging. Epidemiological evidence indicates that up to 40
Parkinson’s disease (PD) is characterized by progressive nigrostriatal dopaminergic degeneration and a dysregulated neuroinflammatory environment. Here, we investigated whether intranigral delivery of a microRNA‑204‑5p mimic (miR‑204-5p) at the time of lesion modulates dopaminergic‑dependent rotational asymmetry, glial morphology, and striatal medium spiny neurons (MSNs) recruitment in a unilateral 6‑OHDA mouse model. Adult C57BL/6 mice received a unilateral striatal 6‑OHDA injection and simultaneous intranigral infusion of a synthetic miR‑204‑5p mimic or vehicle, and apomorphine‑induced rotations, rotarod performance, TH immunohistochemistry, high‑content morphometric analyses of GFAP‑positive astrocytes and IBA1‑positive microglia, and c‑Fos/DARPP‑32 expression were assessed four weeks later. In 6‑OHDA‑lesioned mice, miR‑204-5p treatment significantly reduced apomorphine‑induced contralateral rotations relative to 6‑OHDA alone, while TH‑positive neuron counts in the substantia nigra and TH‑positive fiber density in the striatum remained comparably reduced across all lesioned groups. Intranigral miR‑204-5p delivery in 6‑OHDA‑lesioned animals was associated with increased astrocytic and microglial branching complexity along the nigrostriatal axis and with a higher proportion of striatal DARPP‑32‑positive MSNs expressing c‑Fos during dopaminergic stimulation, without a change in total c‑Fos‑positive cell counts. These findings indicate that miR‑204‑5p mimic administration can modulate glial morphology and apomorphine‑induced rotational asymmetry in a severely denervated nigrostriatal system without detectable dopaminergic neuroprotection as assessed by TH immunostaining. This exploratory study supports further investigation of glial mechanisms in miR-based approaches to PD.
Hydrogen sulfide (H2S), an endogenous gasotransmitter, exerts potent anti-neuroinflammatory effects. Both endogenous and exogenous H2S attenuate cerebral ischemia/reperfusion (I/R) injury by suppressing neuroinflammatory responses. Microglia play a pivotal role in post-ischemic neuroinflammation. Upon activation, microglia polarize toward either the pro-inflammatory M1 phenotype or the anti-inflammatory M2 phenotype. The progression of neuroinflammation is closely associated with M1 polarization, while H2S has been demonstrated to inhibit M1 polarization and promote the protective M2 phenotype. Similarly, astrocytes undergo phenotypic transformation following ischemic stroke, with A1 reactive astrocytes exacerbating neuronal injury and A2 reactive astrocytes exerting neuroprotective effects. Our previous studies have shown that both endogenous and exogenous H2S promote astrocytic polarization toward the neuroprotective A2 phenotype. This review provides a comprehensive overview of ischemic stroke and the anti-neuroinflammatory effects of H2S and its donors in cerebral I/R injury, with particular emphasis on their roles in regulating microglial and astrocytic polarization toward neuroprotective phenotypes. Additionally, we discuss the intracellular signaling pathways involved in H2S-mediated suppression of neuroinflammation. Collectively, this review highlights the therapeutic potential of H2S donors as novel agents for the treatment of cerebral I/R injury. We propose that H2S donors exert their neuroprotective effects primarily through coordinated regulation of microglial and astrocytic polarization toward anti-inflammatory phenotypes, and that this dual-cell targeting strategy represents a viable therapeutic approach for cerebral I/R injury.
Chronic stress-induced neuroinflammation and gut microbiota dysbiosis have been implicated in the pathogenesis of depression. The classic herbal formula Chaihu-Jia-Longgu-Muli Tang (CLM) has been reported to exert antidepressant effects, but the underlying mechanisms remain poorly understood. This study aimed to investigate whether CLM ameliorates depressive-like behavior in chronic restraint stress (CRS)-induced mice and to explore its association with the gut microbiota remodeling, NLRP3 inflammasome signaling, and microglia activation. A mouse model of depression was established through exposure to CRS. Depressive-like behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and open field test (OFT). Hippocampal neuronal damage was evaluated by HE and Nissl staining. Intestinal barrier integrity was examined by HE staining and immunofluorescence staining for ZO-1 and occludin. Colonic and hippocampal levels of pro-inflammatory cytokines were measured by ELISA. Gut microbiota composition was analyzed by 16 S rRNA gene sequencing. Hippocampal M1 microglial polarization and microglial NLRP3 localization were assessed by Iba-1/CD86 and Iba-1/NLRP3 double immunofluorescence staining, and NLRP3 inflammasome-related protein expression was further evaluated by Western blotting. CLM attenuated CRS-induced depressive-like behaviors and hippocampal neuronal damage, restored gut barrier integrity as indicated by increased ZO-1 and occludin expression and reduced colonic IL-6, TNF-α, and IL-1β levels, and reshaped the gut microbiota by increasing SCFA-producing Muribaculaceae, Alloprevotella, and Bacteroides and decreasing Dubosiella and Lactobacillus spp. Exploratory Spearman analyses identified several nominal associations between microbial taxa and behavioral or inflammatory variables; however, these associations did not remain significant after Benjamini-Hochberg FDR correction and should therefore be interpreted as hypothesis-generating. CLM-H also reduced hippocampal CD86⁺/Iba-1⁺ cells, decreased NLRP3+/Iba-1+ co-localization, and reduced NLRP3, caspase-1 p20, and pro-IL-1β expression. CLM-H ameliorates CRS-induced depressive-like behavior and neuronal damage in association with modulation of the gut microbiota composition, NLRP3 inflammasome-related signaling, and microglial activation. These findings support the potential of CLM as a multi-target intervention for depression-related phenotypes, while further causal validation is still required.
