Translational Neurodegeneration最新文献

Parkinson's disease (PD) is increasingly recognized as a multisystem disorder involving pathological α-synuclein (α-syn) accumulation and widespread neuroimmune dysregulation. Microglia, the resident immune cells in the central nervous system (CNS), are pivotal mediators of the bidirectional communication between the CNS and peripheral systems. In addition to sensing neuronal injury and α-syn pathology, microglia dynamically respond to peripheral immune signals, including circulating cytokines, immune cell infiltration, and microbial metabolites, through pattern recognition receptors such as Toll-like and NOD-like receptors. Furthermore, microglia regulate blood-brain barrier integrity, modulate peripheral immune cell recruitment, interact with meningeal lymphatic vessels, and contribute to the propagation of α-syn within the CNS and along the gut-brain axis. However, a comprehensive framework encompassing their diverse roles in peripheral-central immune crosstalk remains underdeveloped. This review synthesizes recent advances elucidating how microglia link the CNS to peripheral immune and metabolic signals in PD. We further highlight microglial contributions to α-syn propagation along the gut-brain axis and discuss how their functional states influence disease progression. A deeper understanding of microglial involvement in this complex neuroimmune interface may inform the development of effective and system-level therapeutic strategies for PD.

Advancements in visualization methods have brought the meningeal lymphatic system (MLS) into the spotlight. The meningeal lymphatic vessels (mLVs) play a vital role in draining cerebrospinal fluid and immune cells, acting as a central hub for immune surveillance in the brain. Age-related morphological and functional declines of mLVs suggest their involvement in the pathogenesis of neurodegenerative disorders (NDDs). In this article, we summarize key discoveries about the MLS over the past decade, highlight the neuro-immune crosstalk in the meninges, and discuss the role of mLVs in both brain homeostasis and neurodegeneration. As a critical regulator of brain function and a potential therapeutic target, the MLS offers a promising avenue for the diagnosis and treatment of NDDs, particularly Alzheimer's Disease.

Background: Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.

Methods: DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.

Results: Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival.

Conclusions: The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.

Background: Alzheimer's disease (AD) is the most prominent form of dementia worldwide. It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner. This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell to cell. Human brain-derived extracellular vesicles (BD-EVs) isolated from the brain-derived fluid of AD patients contain seeds that contribute to this tau pathology spreading. Knowing the rich diversity of EVs, isolation of functional EV sub-populations is required to unravel their implication in the pathophysiology of AD.

Methods: Here, enriched-small EVs (eSEVs) and enriched-large EVs (eLEVs) were isolated from frozen tissues after collagenase enzymatic brain dissociation to guarantee the best EVs' integrity. Then proteomic profiling and tau seeding capacity testing were performed in vitro and in vivo.

Results: BD-EVs were stratified according to their size (eSEVs and eLEVs) and characterized to define new markers specific to EVs in AD. Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature. Notably, AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling, while AD eLEVs proteins were more related to respiratory electron transport and brain immunity. Injection of these vesicles in transgenic mouse brain revealed that the AD-derived eSEVs are more prone than eLEVs to participate in the prion-like propagation and hence represent an interesting therapeutic target.

Conclusion: This study highlights the significant contribution of AD-derived EVs to tau propagation and provides new insights into different roles of EV sub-populations in AD.

Background: In order to elucidate the neuromodulatory mechanisms underlying therapeutic subthalamic deep brain stimulation (DBS), we here reverse-translate a methodological pipeline that integrates neurostimulation effect parameterization and molecular imaging.

Methods: ¹⁸F-fluorodeoxyglucose positron emission tomography was performed in a human-mimicking A53T alpha-synuclein Parkinson's disease rat model and in control rats under both stimulation ON and OFF conditions, with additional CT scans acquired for each rat. Patient-derived approaches-including electrode modeling, electric field estimation, and volume of tissue activated measurement-were applied to assess stimulation effects at the stimulation spot.

Results: We revealed consistent hypometabolism in the ipsilateral subthalamic nucleus, substantia nigra, zona incerta, cerebellum, and entopeduncular nucleus, alongside hypermetabolism in the ipsilateral lateral caudate putamen and globus pallidus externus in A53T rats at the OFF condition. Subthalamic DBS improved motor dysfunction and induced specific metabolic responses that differentiated from controls, including increased metabolism in the ipsilateral subthalamic nucleus, substantia nigra, and zona incerta, and decreased metabolism in the bilateral primary motor and somatosensory area, lateral caudate putamen, and contralateral secondary motor area.

Conclusions: Therapeutic subthalamic DBS activates the target region and modulates global brain function by restoring OFF-state hypometabolism in the ipsilateral subthalamic-substantia nigra loop and by reducing metabolic activity in the bilateral cortico-striatal circuitry. A reverse-translational pipeline is established to study stimulation-induced modulation of brain function, integrating a novel positron emission tomography template aligned with the Waxholm space of Sprague-Dawley rats.

Neurodegenerative diseases (NDDs), including Parkinson's disease and Alzheimer's disease, are major age-related disorders characterized by progressive neuronal degeneration and a decline in cognitive and motor functions. Managing NDDs poses an increasing healthcare challenge as the global population ages. The onset of NDDs is linked to protein misfolding, oxidative stress, dysfunction of mitochondria and lysosomes, and neuroinflammation. Clinical manifestations of NDDs only appear after substantial neuronal damage has already occurred. This underscores the urgent need for accessible tissue biomarkers to enable early diagnosis, disease monitoring and assessment of therapeutic efficacy. The skin has emerged as a valuable peripheral indicator of neurodegeneration, sharing embryological origin, gene expression profiles, protein alterations and cellular dysfunctions with the brain. Notably, pathological protein deposits, which are hallmarks of NDDs, such as beta-amyloid, tau proteins, and oligomeric alpha-synuclein, have been observed in the skin. Increasing evidence links NDDs with various pathological skin conditions, including melanoma and inflammatory diseases. This review aims to explore the potential of the skin as a window into neurodegenerative processes at an early stage, before clinical signs arise. The main advantages of using skin as a source of NDD biomarkers are its accessibility and the minimally invasive sampling methods such as stratum corneum collection, sebum and volatile compounds analysis, and biopsies. Immunohistochemistry and omics approaches applied to skin samples provide valuable insights into NDD pathophysiology and facilitate biomarker discovery for early diagnosis and disease monitoring. NDDs are multisystemic disorders and new findings in skin research highlight the value of peripheral tissues for investigating central nervous system alterations enabling earlier neuroprotective interventions.

Aging is a multifaceted biological process affecting various organ systems. Immunosenescence, a key feature of aging, markedly increases susceptibility to infections, cancers, autoimmune diseases, and also neurodegenerative disorders. Immunosenescence not only accelerates normal aging but also drives the progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the lack of a consensus on the mechanistic hallmarks of immunosenescence presents a major barrier to the development and validation of anti-aging therapies. In this review, we propose 11 hallmarks of immunosenescence: genomic instability, telomere attrition, epigenetic dysregulation, stem cell exhaustion, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, altered intercellular communication, and microbiome dysbiosis. We also elucidate the intricate interplay between immunosenescence and both normal brain aging and neurodegenerative pathologies, highlighting the pivotal involvement of age-related immune dysregulation in the pathogenesis of neurodegenerative disorders. This mechanistic connection is particularly evident in prototypical neurodegenerative conditions such as AD and PD, where immunosenescence appears to significantly contribute to disease progression and phenotypic manifestations. Given that the ultimate goal of immune aging research is to prevent or alleviate age-related diseases, we also discuss potential hallmark-targeting anti-immunosenescence strategies to delay or even reverse normal aging and neurodegeneration.

Background: The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

Methods: AAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.

Results: Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.

Conclusions: This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).

Background: α-Synuclein oligomers (α-synOs) contribute to the initiation and progression of Parkinson's disease (PD) by promoting neuronal death and activating glial cells. Clearing α-synOs while maintaining tissue homeostasis is a promising therapeutic strategy for PD.

Methods: We genetically engineered astrocytes with an anti-α-synO chimeric antigen receptor (CAR) consisting of a single-chain variable fragment targeting α-synOs and a truncated MerTK receptor, to direct their phagocytic activity against α-synOs.

Results: CAR-engineered astrocytes (CAR-A) showed significantly enhanced phagocytosis of α-synOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased the release of pro-inflammatory cytokines by inhibiting the NF-κB and cytokine receptor signaling pathways. Consistently, in situ CAR-A significantly ameliorated the motor and cognitive deficits of A53T mice by clearing α-synOs, creating a non-inflammatory microenvironment and restoring the viability of dopaminergic neurons.

Conclusions: CAR-A-based strategy is an effective treatment for PD-like mouse model. This in situ CAR-A technology provides an innovative and feasible strategy to treat PD and other brain disorders.

Background: Effective therapies for Alzheimer's disease (AD) remain to be developed. APOE4 is the strongest genetic risk factor for late-onset AD. Pericyte degeneration and blood-brain barrier (BBB) disruption are thought to be early biomarkers of AD and contribute to cognitive decline in APOE4 carriers, representing potential therapeutic targets. Our previous studies have shown that pericyte transplantation is one of the most effective strategies for BBB restoration, exhibiting great therapeutic potential for APOE4-related BBB damage and AD phenotypes.

Methods: APOE4/4 mice were treated with pericytes derived from APOE3/3 human induced pluripotent stem cells (hiPSCs). Behavioral tests, AD pathologies, and BBB integrity were assessed. Subsequently, temporal and spatial distribution of the transplanted pericytes was analyzed using tdTomato⁺ lentivirus labeling. Next, therapeutic effects of apoptotic vesicles (ApoVs) generated from APOE3/3 pericytes were evaluated in APOE4/4 pericytes in vitro. Additionally, transcriptomic and proteomic profiling were performed to identify key effector molecules in pericyte-derived ApoVs. Finally, the therapeutic effects of ApoVs derived from pericytes were evaluated in APOE4/4 mice.

Results: Early, multiple transplantations of pericytes derived from APOE3/3 hiPSCs robustly rescued cognitive decline and AD pathologies, restored BBB integrity, and prevented in situ pericyte degeneration in aged APOE4/4 mice. Intriguingly, ApoVs released from the infused cells, rather than the transplanted pericytes, were predominantly distributed in the brain, which were ingested by in situ APOE4/4 pericytes and then promoted functional recovery. We further characterized insulin growth factor-2 (IGF-2) as a key factor in APOE3/3 pericyte-derived ApoVs. Infusion of the in vitro generated ApoVs from APOE3/3 pericytes demonstrated distinct therapeutic effects in APOE4/4 mice, which were reversed by IGF2 knockout.

Conclusions: APOE3/3 pericytes or APOE3/3 pericyte-derived IGF2-rich ApoVs may offer promising therapeutic strategies for APOE4-associated AD.