Translational Neurodegeneration最新文献

The glymphatic system serves as the brain's clearance system. It deteriorates with age and is a significant contributor to the onset and progression of Alzheimer's disease (AD). Modulating cerebrospinal fluid (CSF)-based clearance and targeting key components of the glymphatic system, such as aquaporin-4, can enhance amyloid-beta (Aβ) clearance. Light therapy is emerging as a potential AD treatment approach, which involves the use of visible and near-infrared light at specific wavelengths (630/680/808/850/1070 nm), photosensitive proteins, and sensory stimulation at particular frequencies (e.g., 40 Hz). This phototherapy strategy can broadly influence the intracerebral fluid dynamics, including cerebral blood flow, CSF, and interstitial fluid (ISF), as well as structures related to the glymphatic system, such as vascular endothelial cells, glial cells, and neurons. Additionally, it may directly or indirectly inhibit Aβ accumulation by modulating endogenous small molecules, thereby improving cognitive function. Our previous research demonstrated that 630-nm red light can inhibit Aβ cross-linking by clearing endogenous formaldehyde and promoting ISF drainage. Notably, Aβ accumulation exhibits distinct characteristics at different phases of AD, accompanied by varying features of glymphatic system impairment. In the early stages, deep brain regions are significantly affected, whereas in the late stages, accumulation primarily occurs in the paracentral, precentral, and postcentral cortices. Owing to the limited penetration depth of light, this may pose a challenge to the clinical efficacy of phototherapy. Therefore, different stages of AD may require tailored phototherapeutic strategies. Meanwhile, it is important to acknowledge the ongoing controversies associated with lymphovenous anastomosis, a procedure that targets the glymphatic system. Therefore, this article reviews the characteristics of glymphatic system impairment across various AD stages and the mechanisms by which effective phototherapies modulate the glymphatic system. Potential phototherapeutic strategies corresponding to different stages of Aβ accumulation are also proposed.

Neuroinflammation is a key pathological mechanism underlying neurodegenerative diseases, and intricately interacts with protein glycosylation. Emerging evidence suggests that aberrant glycosylation disrupts immune homeostasis, activates microglia, and promotes the release of inflammatory mediators, thereby exacerbating neuroinflammatory responses. In addition, the inflammatory microenvironment can further dysregulate glycosylation patterns, creating a vicious cycle that amplifies disease pathology. Although the regulatory role of glycosylation in neuroinflammation associated with neurodegenerative diseases has been recognized, the precise molecular and cellular mechanisms remain incompletely understood. This review systematically examines the complex crosstalk between glycosylation and neuroinflammation, with a particular focus on the critical roles of glycosylation in key neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. We explore how glycosylation abnormalities contribute to disease pathogenesis through effects on immune recognition, protein aggregation, and cellular functions. Understanding the molecular underpinnings of these diseases may pave the way for the development of therapeutic strategies targeting glycosylation pathways, ultimately improving clinical outcomes for patients.

Mitochondria produce adenosine triphosphate (ATP), the main source of cellular energy. To maintain normal function, cells rely on a complex mitochondrial quality control (MQC) system that regulates mitochondrial homeostasis, including mitochondrial dynamics, mitochondrial dynamic localization, mitochondrial biogenesis, clearance of damaged mitochondria, oxygen radical scavenging, and mitochondrial protein quality control. The MQC system also involves coordination of other organelles, such as the endoplasmic reticulum, lysosomes, and peroxisomes. In this review, we discuss various ways by which the MQC system maintains mitochondrial homeostasis, highlight the relationships between these pathways, and characterize the life cycle of individual mitochondria under the MQC system.

Background: Dysregulation of the endocannabinoid system (eCBS) and the loss of CB1 receptors (CB1R) in the basal ganglia are well-established hallmarks of Huntington's disease (HD). As a result, significant research efforts have focused on targeting the eCBS to alleviate motor disturbances associated with the disease. Beyond its role in motor control, the eCBS is a complex signaling network critically involved in regulating learning and memory. Despite this, the potential involvement of eCBS dysfunction in the cognitive decline characteristic of HD, often manifested well before motor dysfunction, has remained largely unexplored.

Methods: CB1R expression in the hippocampus was evaluated in both human HD samples and HD mouse models (R6/1 and Hdh^Q7/Q111 models, including both sexes) using Western blotting, immunohistochemistry, and radioligand binding assays. To restore CB1R function, CB1R agonist WIN-55212-2 was systemically administered, or viral vectors encoding CB1R were locally infused into the hippocampus of HD mice. A multidisciplinary approach combining behavioral, biochemical, electrophysiological, and morphological analyses, was employed to investigate the molecular mechanisms underlying the effects of CB1R activation in the context of HD-related cognitive dysfunction.

Results: In both human HD samples and HD mouse models, CB1R protein levels were reduced in the hippocampus, accompanied by structural synaptic alterations and impairment in spatial, recognition and working memory. Moreover, hippocampal depolarization-induced suppression of inhibition was significantly disrupted in R6/1 mice. Administration of WIN-55212-2 successfully restored these synaptic and cognitive deficits. Immunohistochemical analysis revealed that the CB1R decrease was specifically localized to GABAergic interneurons within the hippocampus. Notably, targeted restoration of CB1R expression in these interneurons via viral vector delivery was sufficient to rescue hippocampal-dependent memory deficits in HD mice.

Conclusion: This study suggests that impaired CB1R function in hippocampal GABAergic interneurons contributes to memory dysfunction in HD.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive decline of cognitive functions, yet its underlying aetiology remains elusive. While amyloid-β (Aβ) and tau pathologies have been extensively studied, emerging evidence suggests that metal and especially copper dyshomeostasis may also play a crucial role in the pathogenesis of AD. This review explores the intricate relationship between copper and AD, shedding light on the multifaceted mechanisms through which copper dysregulation contributes to neurodegeneration. We delve into the impact of copper ions on Aβ aggregation, tau phosphorylation, and oxidative stress, providing a comprehensive overview of the molecular pathways involved. Furthermore, we discuss the interplay between different brain cell types and the impact Cu dysregulation may have on them. The therapeutic implications of targeting copper dysregulation for AD treatment are also addressed, emphasizing the potential of copper-modulating agents in ameliorating cognitive decline. In summary, this review discusses copper dyshomeostasis as a central player in the intricate tapestry of AD pathology, offering new insights and avenues for therapeutic interventions.

Background: Alzheimer's disease (AD) is a neurodegenerative disease with major symptoms including memory and learning deficits. Neuroinflammation associated with reactive microglia promotes AD progression. These reactive microglia secrete prostaglandins, which are synthesized through the enzymatic activity of cyclooxygenase (COX)-1 and COX-2. Here, we aimed to elucidate the specific mechanisms of COX1 in AD pathogenesis and its interactions with neuroinflammatory processes.

Methods: We conducted backcrossing between COX-1 knockout (KO) and 5 × FAD mice to evaluate the effect of COX-1 deficiency on neuroinflammation. In addition, single-cell sequencing and microarray datasets from public databases and ingenuity pathway analysis in vitro were employed to explore gene expression profiles in the brains of AD mice.

Results: We identified a significant upregulation of COX-1 in 5 × FAD mice, with expression specifically localized to microglia in an age-dependent manner. Additionally, COX-1 KO alleviated neuroinflammation and accumulation of Aβ plaques, subsequently improving cognitive behavior in 5 × FAD mice. Moreover, microglia exhibited an amoeboid morphology in 5 × FAD mice, whereas in age-matched 5 × FAD/COX-1 KO mice, microglia had a ramified appearance. Additionally, our study demonstrated a pharmacological approach that inhibits the prostaglandin E2 (PGE2)/EP2 receptors via inhibition of the cAMP-PKA-NFκB-p65 pathway and NLRP3 inflammasome activation, producing similar beneficial effects as observed in COX-1 KO mice.

Conclusion: Our findings indicate that targeting the COX-1/PGE2/EP2 signaling pathway may alleviate neuroinflammation and impede AD progression. Moreover, the EP2 receptor presents a promising pharmacological target for mitigating the pathological effects associated with COX-1 activity in AD patients.

Background: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD.

Methods: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1).

Results: PPR@siBACE1 crossed the blood-brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice.

Conclusions: This study provides a reliable delivery platform for gene therapies for AD.

Proper brain function and overall health critically rely on the bidirectional communications among cells in the central nervous system and between the brain and other organs. These interactions are widely acknowledged to be facilitated by various bioactive molecules present in the extracellular space and biological fluids. Extracellular vesicles (EVs) are an important source of the human neurosecretome and have emerged as a novel mechanism for intercellular communication. They act as mediators, transferring active biomolecules between cells. The fine-tuning of intracellular trafficking processes is crucial for generating EVs, which can significantly vary in composition and content, ultimately influencing their fate and function. Increasing interest in the role of EVs in the nervous system homeostasis has spurred greater efforts to gain a deeper understanding of their biology. This review aims to provide a comprehensive comparison of brain-derived small EVs based on their epigenetic cargo, highlighting the importance of EV-encapsulated non-coding RNAs (ncRNAs) in the intercellular communication in the brain. We comprehensively summarize experimentally confirmed ncRNAs within small EVs derived from neurons, astrocytes, microglia, and oligodendrocytes across various neuropathological conditions. Finally, through in-silico analysis, we present potential targets (mRNAs and miRNAs), hub genes, and cellular pathways for these ncRNAs, representing their probable effects after delivery to recipient cells. In summary, we provide a detailed and integrated view of the epigenetic landscape of brain-derived small EVs, emphasizing the importance of ncRNAs in brain intercellular communication and pathology, while also offering prognostic insights for future research directions.

Background: Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy.

Methods: We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry.

Results: Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations.

Conclusion: Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.