Translational Neurodegeneration最新文献

Alzheimer's disease (AD) is a major neurodegenerative disorder that causes severe cognitive decline and poses a significant burden on global health systems. Despite extensive research, effective treatments to stop neurodegeneration or promote neuronal regeneration in AD remain elusive. Psychoactive substances as modulators of neurophysiological functions, have received increased attention in research. The main psychoactive agents, such as central nervous system depressants and stimulants, cannabinoids, psychedelics, opioids and ketamine, are being explored for their abilities to enhance learning and cognitive performance and potential neurorestorative functions. In this paper, we review the molecular mechanisms and therapeutic potential of psychoactive substances in AD, in the aim to guide future research directions.

Background: Meningeal lymphatic drainage is crucial for the clearance of amyloid β (Aβ), supporting the maintenance of brain homeostasis. This makes it a promising therapeutic target for Alzheimer's disease (AD). Long-term exercise can reduce the risk of AD; however, the underlying mechanism is not fully understood. In this study, we investigated whether exercise alleviates AD-related pathological changes by improving meningeal lymphatic drainage and its potential mechanisms.

Methods: The morphological and functional features of meningeal lymphatic vessels, as well as Aβ and reactive gliosis in the brain, were compared between 6.5-month-old 5 × FAD mice with or without 1 month of treadmill exercise. RNA sequencing, protein interactions analysis, gene knockdown mediated by adeno-associated virus, and lymphatic endothelial cell culture were conducted to investigate the mechanism underlying exercise-induced meningeal lymphatic vessel plasticity in 5 × FAD mice.

Results: The structural integrity of meningeal lymphatic vessels was compromised in 5 × FAD mice, compared with the wild-type mice. Treadmill exercise increased the diameter and the drainage capacity of the meningeal lymphatic vessels, reduced Aβ deposition, reactive gliosis and astrocyte senescence in the hippocampus and frontal cortex, and improved cognitive function of 5 × FAD mice. Mechanistically, thrombospondin-1 (TSP-1) exacerbated the inhibitory effect of Aβ on lymphatic vessel formation and plasticity through interactions with CD36 and CD47, respectively. Exercise decreased the expression of TSP-1 in reactive astrocytes of AD mice by downregulating eleven-nineteen lysine-rich leukemia-associated factor 2 (EAF2), a protein that facilitates the transcription of the TSP-1-encoding gene Thbs-1 by binding p53. Ultimately, we found that hippocampal astrocyte-specific knockdown of Thbs-1 or Eaf2 enhanced meningeal lymphatic drainage and alleviated AD-like pathology in the hippocampus of 5 × FAD mice.

Conclusions: Long-term exercise protects against AD by enhancing the plasticity and drainage of meningeal lymphatic vessels through downregulation of the EAF2-p53-TSP-1 pathway associated with reactive astrocytes.

Background: Dorsal nigral hyperintensity (DNH) abnormality associated with excessive iron deposition in the substantia nigra, is recognized as an imaging characteristic of Parkinson's disease (PD) and can be effectively visualized using 7T MRI. This study was aimed to develop and validate the optimal DNH assessment method as a biomarker for PD, idiopathic rapid eye movement sleep behavior disorder (iRBD), and Parkinson-plus syndromes, and to explore the nigral iron deposition patterns in these diseases.

Methods: Three-dimensional gradient-echo T2*-weighted images were acquired by 7T MRI from a total of 402 patients and 100 healthy controls (HCs) in two independent cohorts (development and validation cohorts). Seven methods, including four dichotomous methods and three DNH rating scales, were used to assess DNH and evaluate their diagnostic performance. R2* mapping and principal component analysis were performed to assess nigral iron deposition patterns.

Results: Bilateral DNH detection rates in the development cohort were 22.6% for early-stage PD, 3.7% for advanced PD, 93.5% for iRBD, 5.7% for MSA-parkinsonian type, 78.8% for MSA-cerebellar type, 11.8% for progressive supranuclear palsy (PSP), and 100% for HC, with similar rates in the validation cohort. A cut-off of 6 on the 6-point visibility scale demonstrated a 100% accuracy for diagnosing early-stage PD in both the development and the validation cohorts. This scale exhibited moderate differential diagnostic performance between early-stage PD and iRBD (area under the curve [AUC] = 0.940) or MSA-C (AUC = 0.892). Iron deposition was predominantly in the dorsal and posterior substantia nigra of PD and PSP, the intermediate and posterior substantia nigra of MSA-P, and the ventral substantia nigra of MSA-C.

Conclusion: DNH may be preserved in approximately one-quarter of early-stage PD and most MSA-C cases. The 6-point visibility scale on 7T effectively distinguished PD from HC, iRBD, and MSA-C. The nigral iron deposition pattern in PD may help distinguish PD from MSA-P and MSA-C, although it overlaps with that of PSP.

Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation of α-synuclein (α-syn) and tau proteins, respectively. These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies. Recent advancements in passive immunotherapies, notably the FDA approval of the amyloid-beta (Aβ)-targeting antibody lecanemab, have sparked new hope in directly targeting pathological proteins. However, unlike the extracellular Aβ pathology, immunotherapies aimed at α-syn and tau, which predominantly form intracellular inclusions, face substantial challenges. To date, the therapeutic efficacy of five α-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies. These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits, but have not yielded significant clinical improvements in symptoms or measurable biomarkers. Therefore, a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future. In this review, we examine existing passive immunotherapeutic strategies targeting α-syn and tau, specifically in patients with Alzheimer's disease and Parkinson's disease. Lessons learned from initial trial failures are also discussed, including refinement of animal models, inclusion and stratification of participants, improvement of clinical evaluations, and development of biomarkers. Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies, we further explore the potential of combined therapies targeting co-pathologies, offering novel insights for future therapeutic development against these neurodegenerative disorders.

Background: Epidemiological studies have revealed increased Parkinson's disease (PD) risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I (CI) function and causing dopaminergic neuronal loss in the nigrostriatal region. However, the pathway(s) through which MPTP impairs mitochondrial CI function remain to be elucidated. In this study, we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP.

Methods: Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation, were intraperitoneally injected with either MPTP or saline. In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation. Movement performance, mitochondrial function, and protein acetylation were evaluated.

Results: MPTP exposure, both in vitro and in vivo, disrupted the AMPK-SENP1-Sirt3 axis, leading to impairment of mitochondrial function. Specifically, MPTP suppressed activation of AMPK, impeding the entry of SENP1 into the mitochondria. The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3, which inhibited its deacetylase activity. This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5, which resulted in reduced CI activity and inhibition of mitochondrial function, and eventually dopaminergic neuronal death. In this pathway, sustained deSUMOylation mutation of Sirt3 (K223R in mice, K288R in humans) mitigated the impact of MPTP on mitochondrial dysregulation, as well as dopaminergic neuronal death and behavioral deficits.

Conclusion: The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype, which provide valuable insights into the mechanisms of PD pathogenesis.

Background: Despite increasing in vitro research, direct evidence of how abnormal α-synuclein (α-Syn) dysregulates vesicular transport and synaptic function in the human brain is lacking.

Methods: We performed a transcriptome analysis using brain tissues from a multiple system atrophy (MSA) mouse model, which develops human α-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection. We then performed histologic and biochemical analyses using brain samples from 71 human cases (Parkinson's disease, n = 10; dementia with Lewy bodies [DLB], n = 19; MSA, n = 15; control: n = 27), a human blood sample (control: n = 1), and cultured cells.

Results: Based on the transcriptome of the MSA mouse model, we identified 10 vesicular transport proteins, including synaptotagmin 13 (SYT13), that might interact with α-Syn. Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis, only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions. Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylated α-Syn than with endogenous α-Syn. Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylated α-Syn, SYT1, and the soluble N-ethylmaleimide-sensitive attachment protein receptor (SNARE) complexes. Filter trap assays revealed interactions between SYT13 and soluble toxic β-sheet-rich α-Syn oligomers. Furthermore, fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA. Notably, a correlation was observed between the levels of SYT13 and aggregated α-Syn at the synapses. SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells. SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release. Consistently, the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls.

Conclusions: Abnormal α-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies. Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.

Background: Pathologic heterogeneity is a hallmark of Lewy body dementia (LBD), yet the impact of Lewy pathology on co-pathologies is poorly understood. Lewy pathology, containing α-synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimer's disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both α-synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between α-synuclein, tau, and granulovacuolar degeneration.

Methods: We developed a mouse model of limbic-predominant α-synucleinopathy by stereotactic injection of mouse α-synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of α-synuclein pathology with tau and GVB formation.

Results: Our model displayed widespread α-synuclein pathology with a limbic-predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of α-synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1δ-positive granules, established markers of GVBs, which suggests a link between tau accumulation and GVB formation. Despite this observation, GVBs were also detected in tau-deficient mice following PFF injection, suggesting that pathological α-synuclein alone is sufficient to elicit GVB formation.

Conclusions: Our findings support that α-synuclein pathology can independently elicit granulovacuolar degeneration. The frequent co-accumulation of tau and GVBs suggests a parallel mechanism of cellular dysfunction. The ability of α-synuclein pathology to drive GVB formation in the absence of tau highlights the broader relevance of this process to neurodegeneration with relevance to the pathobiology of LBD.

Background: Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for > 95% of all Alzheimer's disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear.

Methods: AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague-Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test.

Results: YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects.

Conclusions: These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD.