Translational Neurodegeneration最新文献

The diagnosis of neurodegenerative diseases (NDDs) remains challenging, and existing therapeutic approaches demonstrate little efficacy. NDD drug delivery can be achieved through the utilization of nanostructures, hence enabling multimodal NDD theranostics. Nevertheless, both biomembrane and non-biomembrane nanostructures possess intrinsic shortcomings that must be addressed by hybridization to create novel nanostructures with versatile applications in NDD theranostics. Hybrid nanostructures display improved biocompatibility, inherent targeting capabilities, intelligent responsiveness, and controlled drug release. This paper provides a concise overview of the latest developments in hybrid nanostructures for NDD theranostics and emphasizes various engineering methodologies for the integration of diverse nanostructures, including liposomes, exosomes, cell membranes, and non-biomembrane nanostructures such as polymers, metals, and hydrogels. The use of a combination technique can significantly augment the precision, intelligence, and efficacy of hybrid nanostructures, therefore functioning as a more robust theranostic approach for NDDs. This paper also addresses the issues that arise in the therapeutic translation of hybrid nanostructures and explores potential future prospects in this field.

Alzheimer's disease (AD) is a progressive neurological disorder that primarily impacts cognitive function. Currently there are no disease-modifying treatments to stop or slow its progression. Recent studies have found that several peripheral and systemic abnormalities are associated with AD, and our understanding of how these alterations contribute to AD is becoming more apparent. In this review, we focuse on amyloid‑beta (Aβ), a major hallmark of AD, summarizing recent findings on the source of brain-derived Aβ and discussing where and how the brain-derived Aβ is cleared in vivo. Based on these findings, we propose future strategies for AD prevention and treatment, from a novel perspective on Aβ metabolism.

The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

The deposition of abnormal tau protein is characteristic of Alzheimer's disease (AD) and a class of neurodegenerative diseases called tauopathies. Physiologically, tau maintains an intrinsically disordered structure and plays diverse roles in neurons. Pathologically, tau undergoes abnormal post-translational modifications and forms oligomers or fibrous aggregates in tauopathies. In this review, we briefly introduce several tauopathies and discuss the mechanisms mediating tau aggregation and propagation. We also describe the toxicity of tau pathology. Finally, we explore the early diagnostic biomarkers and treatments targeting tau. Although some encouraging results have been achieved in animal experiments and preclinical studies, there is still no cure for tauopathies. More in-depth basic and clinical research on the pathogenesis of tauopathies is necessary.

Background: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.

Methods: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test.

Results: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits.

Conclusions: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.

There is increasing evidence for blood-brain barrier (BBB) alterations in Parkinson's disease (PD), the second most common neurodegenerative disorder with rapidly rising prevalence. Altered tight junction and transporter protein levels, accumulation of α-synuclein and increase in inflammatory processes lead to extravasation of blood molecules and vessel degeneration. This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration, which contribute to neurodegeneration. Toxin exposure or α-synuclein over-expression in animal models has been shown to initiate similar pathologies, providing a platform to study underlying mechanisms and therapeutic interventions. Here we provide a comprehensive review of the current knowledge on BBB alterations in PD patients and how rodent models that replicate some of these changes can be used to study disease mechanisms. Specific challenges in assessing the BBB in patients and in healthy controls are discussed. Finally, a potential role of BBB alterations in disease pathogenesis and possible implications for therapy are explored. The interference of BBB alterations with current and novel therapeutic strategies requires more attention. Brain region-specific BBB alterations could also open up novel opportunities to target specifically vulnerable neuronal subpopulations.

Adult hippocampal neurogenesis (AHN) is affected by multiple factors, such as enriched environment, exercise, ageing, and neurodegenerative disorders. Neurodegenerative disorders can impair AHN, leading to progressive neuronal loss and cognitive decline. Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory. Interestingly, specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models. Despite these advancements, the precise mechanisms by which exercise mimetics induce AHN remain partially understood. Recently, some novel exercise molecules have been tested and the underlying mechanisms have been proposed, involving intercommunications between multiple organs such as muscle-brain crosstalk, liver-brain crosstalk, and gut-brain crosstalk. In this review, we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders. Opportunities, challenges, and future directions in this research field are also discussed.

Background: Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression.

Methods: We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model.

Results: We found that the activity of dorsal raphe nucleus serotonin neurons (DRN^5-HT) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN^5-HT-dCA1^CaMKII) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN^5-HT-dCA1^CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT_1BR) and 4 (5-HT₄R). Pharmacological activation of 5-HT_1BR or 5-HT₄R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN^5-HT-dCA1^CaMKII neural circuit to improve synaptic plasticity.

Conclusions: These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.