Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD. hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3 × Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9 months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal Aβ levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients. The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3 × Tg-AD mice and reduced hippocampal Aβ levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3 × Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability. hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.
Neurodegenerative diseases are increasingly linked to abnormalities in the gut–brain axis, yet the local intestinal interface at which luminal and mucosal perturbations are related with the central nervous system remains poorly defined. The gut neuroepithelial unit (GNU) is proposed as a localized mucosal signalling interface composed of sensory epithelial cells, enteric neurons, glia and adjacent immune-stromal elements that detect, encode and route intestinal information into neural, endocrine and immune outputs. This framework shifts the intestine from being a diffuse upstream modifier of brain pathology to a mesoscopic unit through which microbial products, barrier dysfunction, inflammatory cues and metabolic signals are transformed into disease-relevant gut-to-brain communication. Particularly, in Parkinson’s disease and Alzheimer’s disease, the GNU may function as a conditional interface that amplifies, filters or biases peripheral signals before they engage central circuits. The GNU therefore provides a tractable framework for mechanistic dissection, translational stratification and peripheral therapeutic targeting in neurodegeneration.
The brain was long been regarded as an immune-privileged organ with a lack of lymphatic drainage, partly because of the absence of parenchymal lymphatic vessels. This long-held doctrine has been challenged by recent advancements in central lymphatic vascular biology. The central drainage network, which consists of the glymphatic system, meningeal lymphatic vessels, and cranial perineural drainage pathways, plays a crucial role in the clearance of metabolic brain waste and the maintenance of brain homeostasis. Furthermore, the meninges and brain perivascular spaces are rich in immune cells that regulate neuronal activities and diverse behaviors through secretion of cytokines. Dysfunction of the central lymphatic network is widely observed in natural aging and neurodegenerative disorders, which is characterized by mislocalization of aquaporin-4 on astrocytic endfeet, impairment of lymphatic valvular integrity, and alterations in the proportion and phenotype of meningeal immune cells. In this review, we provide a comprehensive overview of the anatomical foundations, molecular regulatory mechanisms, and physiological functions of this system. We summarize the pathological roles of the central lymphatic network across neurodegenerative conditions and discuss emerging clinical assessment frameworks based on multimodal imaging and liquid biomarkers. We also highlight promising therapeutic strategies, such as restoring meningeal lymphatic function, targeting glymphatic drainage, and modulating the meningeal immune microenvironment. Elucidating the dynamics of the central lymphatic network will reshape our understanding of brain homeostasis, paving the way for novel diagnostic and therapeutic strategies for neurodegenerative diseases. Future research should focus on translating fundamental findings into clinical applications, thereby accelerating the transition from basic research to clinical practice.
Biomolecular condensates formed via liquid–liquid phase separation (LLPS) are increasingly recognised as dynamic organisers of intracellular biochemistry, particularly in neurons where spatially restricted signalling, RNA metabolism, and proteostasis are essential. Aberrant phase transitions of disease-associated proteins, including TDP-43, FUS, tau, and α-synuclein, contribute to protein aggregation and neurodegenerative pathology. Beyond protein-intrinsic sequence features, metabolic state has emerged as an important contextual regulator of condensate assembly, material properties, and liquid-to-solid maturation. Metabolic cues, including ATP availability, NAD+/NADH balance, redox state, lipid composition, enzyme-mediated post-translational modifications, and cellular stress responses, can influence the phase behaviour across biochemical, cellular, and disease-model systems. However, direct causal evidence in neurons, animal models, and human neurodegenerative diseases remains uneven and protein-specific. Here, we review LLPS in neurodegenerative disorders from the metabolic perspective, distinguishing established mechanisms from plausible but incompletely validated links. We discuss how pathological condensates may impair RNA metabolism, synaptic function, proteostasis, and cognition, and critically evaluate emerging therapeutic strategies that aim to modulate aberrant phase behaviour. This review therefore provides a cautious framework in which metabolic dysregulation is considered a potential upstream contributor to pathological phase transitions rather than an established master regulator.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage—inflammatory activation—autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.
Abstract Background Huntington’s disease (HD) is a genetically dominant neurodegenerative disorder characterized by several pathological mechanisms, including the disruption of brain cholesterol homeostasis. In several HD animal models, brain cholesterol biosynthesis and levels are reduced. Since circulating cholesterol cannot reach the brain, providing exogenous cholesterol has been shown to improve HD phenotypes. However, the methods used for cholesterol delivery were invasive and not easily transferable to clinical practice. Methods Cholesterol-enriched liposomes were developed by using freeze-and-thaw methods and were administered to R6/2 mice through a single or repeated intranasal administrations. Deuterated-cholesterol was used to discriminate exogenous from endogenous cholesterol. Exogenous cholesterol accumulation and distribution, as well as the levels of cholesterol precursors and metabolites, were measured using mass spectrometry. Behavioral tests, real-time PCR analysis, and immunostaining of mutant HTT (muHTT) aggregates were performed to verify the therapeutic effects of liposomes. Plasma neurofilament levels were measured by Simoa-Quanterix assay. Results We developed and characterized freeze-and-thaw liposomes. Then, we demonstrate that the exogenous cholesterol can spread throughout the entire brain following intranasal administration of cholesterol-enriched liposomes. Furthermore, repeated intranasal treatments with liposomes result in a full restoration of cognitive decline, and delayed the onset of coordination and motor impairment as well as the loss of muscular strength in the early stages of the disease. Cholesterol supplementation also reduced the plasma level of neurofilament light chain and promoted the clearance of muHTT aggregates. Conclusions The findings support the effectiveness of cholesterol supplementation as a therapeutic strategy for HD and indicate the translational potential of nose-to-brain cholesterol delivery.
Abstract Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer’s and Parkinson’s diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR–neurodegeneration axis at its mechanistic roots.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common age-related neurodegenerative disorders. Allen Human Brain Atlas (AHBA) provides high-resolution transcriptomic data across 102 brain regions with multi-site sampling from healthy controls, promoting the use of brain-wide transcriptomic data for imaging transcriptomics and cross-modal model construction. Increasingly, researchers are utilizing brain-wide transcriptomic datasets to investigate the transcriptome correlates of the neuroimage phenotypes in AD and PD. Leveraging the AHBA, researchers have analyzed the transcriptomic correlations of regional susceptibility to Aβ deposition, tau deposition, α-synuclein propagation, and disease-related multiple-dominal neuroimage phenotypes. These studies revealed that transcriptomic pathways related to metabolism, immunity, neurotransmission, and synaptic function play critical roles in the neuroimage phenotype of AD and PD. By incorporating transcriptomic data modeling, subsequent analyses further confirmed that transcriptomic differences provide the molecular basis for the varying susceptibility observed across brain regions. The analytical approaches of imaging transcriptomics, multimodal data integration strategies, and model construction methods used in AD and PD provide a novel perspective for exploration and can be extended to other neurodegenerative diseases. Future research is expected to utilize brain-wide transcriptomic data to uncover the gene expression mechanisms driving neurodegenerative disease phenotypes.
BackgroundAccumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression.MethodsTo model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent "prion-like" spreading of aggregates.ResultsThe internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival.ConclusionsOur study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.
Astrocytes, the most abundant glial cells in the central nervous system, play increasingly recognized roles in metabolic regulation beyond their classical supportive functions. This review summarizes current understanding of astrocyte morphological and molecular heterogeneity, with emphasis on regional metabolic properties across different brain areas. We discuss the primary forms and functional significance of astrocyte-neuron metabolic coupling, focusing on glucose, lipid, and glutamate metabolism, lactate shuttling, as well as the mitochondrial reactive oxygen species signaling. Furthermore, we integrate emerging evidence from animal and preclinical studies linking astrocyte-neuron metabolic coupling to ageing-related diseases. Collectively, these findings highlight how astrocyte–neuron interactions sustain physiological homeostasis and contribute to pathological manifestations, underscoring their significance in both health and ageing-related diseases.
Extensive research evidence indicates that neuronal immune receptors play a critical role in Alzheimer's disease (AD). However, it remains unclear how these receptors convert extracellular signals into cellular pathological changes. Proteolytic cleavage of membrane receptors serves as an unconventional pathway for reprogramming cellular functions, and the cleaved fragments often play important roles within the cell. Whether immune receptors mediate their effects in AD through this cleavage-dependent signaling mechanism remains to be clarified. We performed proteomic screening of human cerebrospinal fluid to identify cleaved membrane proteins. Cleavage events were validated in postmortem AD brains, primary neurons, and APP/PS1 mice by immunoprecipitation, liquid chromatography-tandem mass spectrometry (LC–MS/MS), and immunofluorescence. Functional impacts were assessed through cathepsin D maturation assays, Retention Using Selective Hooks (RUSH) systems, live imaging of axonal transport, and behavioral tests (e.g., Barnes maze and fear conditioning). Therapeutic potential was evaluated by inhibiting the paired immunoglobulin-like receptor B (PirB) cleavage and overexpression of the GAT domain of Golgi-associated, gamma adaptin ear-containing, ARF binding protein 3 (GGA3). This study identified a pathogenic proteolytic pathway in AD patients and mouse models, which cleaves PirB, a mouse ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), upon Aβ exposure, generating a C-terminal fragment (PirB-CTF) that accumulated in the Golgi apparatus via retrograde transport. PirB-CTF bound to the GAT domain of GGA3, disrupting Golgi transport, impairing lysosomal maturation, and compromising anterograde synaptic vesicle transport. Inhibiting PirB cleavage or overexpressing GGA3-GAT restored Golgi function, reduced Aβ plaque burden and tau phosphorylation, and rescued memory deficits. Our study revealed a non-canonical pathway in which proteolytic cleavage repurposes PirB into an intracellular disruptor of Golgi trafficking, directly coupling immune receptor activation to organelle dysfunction in AD. The PirB-CTF/GGA3 interface represents a promising therapeutic target for mitigating trafficking deficits and cognitive decline in neurodegenerative disorders.
The definition of Parkinson’s disease (PD) is undergoing a profound transformation from a “clinical syndrome” to a “biological entity”, with development of two objective biological classification systems, the NSD-ISS (Neuronal Alpha-Synuclein Disease Integrated Staging System) and the SynNeurGe framework. Multimodal diagnostic tools further improve the detection of PD. This review synthesizes advances in three key domains of PD detection. First, fluid and tissue biomarkers, particularly using α-synuclein (αSyn) seed amplification assays, allow detection of synucleinopathy in cerebrospinal fluid, blood, saliva, and skin. This supports pathological diagnosis and differential classification. Extracellular vesicles provide cell-type-specific cargo profiles, while neurofilament light chain indicates neuroaxonal injury. Second, neuroimaging captures in vivo pathology. MRI identifies nigral degeneration (nigrosome-1 loss, iron accumulation, neuromelanin depletion), MRS reveals metabolic and neurotransmitter imbalances, and αSyn positron emission tomography tracers enable direct visualization of aggregation. Third, digital biomarkers derived from wearable devices, videos, and audios quantify real-world motor and non-motor symptoms, enabling continuous, ecological monitoring. Integration of these complementary biomarker streams is essential for biological definition and stratification of PD patients, and development of targeted therapies. Standardization of assays, multicenter validations, and clear guidance on who should be tested, when testing is appropriate, and how results should inform diagnosis, stratification, or monitoring are required for the translation of these methods into clinical practice in PD.
The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.
Abstract As the global population ages, neurodegenerative and neuroinflammatory diseases are becoming a rapidly growing public health challenge, with available interventions remaining largely symptomatic and often only modestly affecting long-term disease progression. Therapies involving mesenchymal stromal cells (MSCs) have attracted substantial attention as a potential clinical therapeutic strategy across chronic central nervous system (CNS) disorders, due to their multifaceted ability to modulate immune response and confer neuroprotection. While initially explored for their multilineage differentiation potential, MSCs are now predominantly recognized for their paracrine functions, including secretion of soluble factors and extracellular vesicles. These acellular mediators induce diverse neuroprotective effects by attenuating neuroinflammation, stabilizing the blood–brain barrier, reprogramming glial and lymphocyte activity, and delivering regulatory microRNAs that modulate neuronal apoptosis and inflammatory gene networks. In this review, we summarize molecular evidence from in vitro and in vivo preclinical models, and early clinical investigations that demonstrate how tissue source and immunobiological plasticity shape the efficacy of MSCs. We further highlight emerging trends toward acellular MSC-derived therapies, offering a mechanistically versatile platform for therapeutic interventions for common neurodegenerative and neuroinflammatory disorders of the CNS, particularly Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, a primary autoimmune demyelinating disorder. Graphical abstract
BACKGROUND:Medial temporal lobe hyperexcitation or seizures originating from the hippocampus are frequently observed in Alzheimer's disease (AD) patients, contributing to accelerated cognitive decline. As the hippocampus is an early vulnerable area of tau pathology, the mechanisms by which abnormal tau aggregation promotes temporal lobe epilepsy (TLE) remain poorly understood. METHODS:We investigated the role of AD-like hippocampal tau aggregation in neuronal hyperexcitation using transgenic (Tg) tau-driven mice. Effects of tau aggregation on intracellular calcium dynamics were assessed by calcium imaging. Neuronal/network hyperexcitability and seizure susceptibility were evaluated through patch-clamp electrophysiology, 18F-FDG PET/CT, and optogenetic induction. A tetracycline-controlled (Tet-on) system in Tg hTau368 mice enabled spatiotemporal induction of tau pathology to investigate its interactions with calbindin-D28k (CB) and synaptic proteins. Adeno-associated virus (AAV)-mediated CB supplementation in hippocampal CA1 and dentate gyrus (DG) excitatory neurons was performed to correct hyperexcitability and cognitive deficits. Finally, the relationship between CB and disease progress was analyzed using an AD public database. RESULTS:Tau accumulation in the hippocampal CA1/DG CaMKII-positive excitatory neurons reduced CB expression with disruption of calcium homeostasis. This dysregulation increased neuronal excitability, diminished synaptic protein levels, and increased seizure susceptibility and cognitive impairment. AAV-driven CB restoration in CA1/DG neurons attenuated both hyperexcitability and cognitive deficits. In the brains of AD patients, reduced CB expression was associated with cognitive deterioration and advanced disease stages. CONCLUSIONS:Tau aggregation drives calcium dysregulation and hippocampal neuronal hyperexcitation through reducing CB expression. These results establish a potential mechanistic link between tauopathy and TLE pathogenesis in AD, providing evidence for CB as a promising therapeutic target for mitigating seizure risk and related cognitive decline in AD.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of misfolded α-synuclein, yet the underlying mechanisms remain incompletely understood. Over the past two decades, genetic discoveries have highlighted the convergence of multiple familial PD genes on the autophagy-lysosome pathway (ALP), a key cellular system responsible for the degradation and recycling of intracellular components. Recent studies have further revealed that components of the ALP not only mediate the clearance of α-synuclein aggregates but also, under certain pathological conditions, contribute to their propagation via lysosomal exocytosis or secretory autophagy. The precise functions of autophagy are highly context-dependent, with neuronal and glial cells exhibiting distinct ALP dynamics that shift with development, stress, and aging. In this review, we summarize current knowledge on the physiological regulation of autophagy in the brain and critically examine its involvement in PD pathogenesis, incorporating mechanistic insights from familial models and emerging evidence from sporadic PD. We also explore translational implications, focusing on efforts to identify ALP-related biomarkers in cerebrospinal fluid and urine, and on the therapeutic potential of modulating ALP activity. Although the causality between ALP dysfunction and PD remains elusive, mounting evidence supports its contribution to disease progression, particularly through impaired lysosomal homeostasis and disrupted intracellular trafficking. Future research should aim to define cell type-specific ALP alterations, clarify the bidirectional interactions between α-synuclein and autophagic machinery, and develop in vivo tools to monitor autophagy activity and secretory signatures. A deeper understanding of these processes will be crucial for refining PD models, discovering robust fluid biomarkers, and designing targeted therapies capable of modifying disease trajectory.
BACKGROUND:Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease (AD), characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein, named AcMet11-Tau. METHODS:We identified AcMet11-Tau by further analyses of previous proteomic data (capillary liquid chromatography-tandem mass spectrometry). We developed a monoclonal antibody, termed 2H2D11, by hybridoma method. The specificity of 2H2D11 was validated by ELISA, Western blot and immunohistochemistry. Expression of AcMet11-Tau in transgenic mouse model of Tau pathology and postmortem brain tissues was analyzed by ELISA and/or immunohistochemistry. Overexpression of AcMet11-Tau in the mouse brain was achieved by stereotaxic injections of lentiviral vectors carrying the coding sequence in the hippocampus. To neutralize AcMet11-Tau, transgenic mice received repeated intraperitoneal immunizations with either 2H2D11 or control antibody. The effects on Tau pathology were assessed by immunohistochemistry, qPCR, and behavioral assays. RESULTS:Using 2H2D11, the newly developed antibody specifically targeting the AcMet11-Tau variant, we demonstrated that this species accumulated early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments revealed that expression of this truncated Tau species exacerbated Tau pathology in the transgenic mice, whereas targeted immunotherapeutic with the specific 2H2D11 antibody significantly reduced pathological Tau accumulation and prevented associated memory impairments. CONCLUSION:These findings position this newly identified Tau variant as a marker of neurofibrillary degeneration and a Tau species that contributes to disease-associated pathological processes, supporting its potential as a therapeutic target in Tau-related disorders, notably AD.
The field of regenerative medicine for Parkinson’s disease (PD) has reached a pivotal moment. After decades of preclinical research, recent first-in-human clinical trials demonstrated that cell replacement therapy using stem cell-derived dopaminergic neurons is not only feasible and safe but also shows promising signs of efficacy. Here we analyze three landmark 2025 studies, including the phase I/II trial of allogeneic induced pluripotent stem cell-derived dopaminergic progenitors, that mark a significant leap forward for PD therapy. We discuss principles underpinning the therapy, the historical context of fetal tissue transplants, findings from recent trials, and critical challenges. The convergence of robust cell manufacturing, precise stereotactic surgery, and advanced neuroimaging provides compelling evidence that stem cell-based therapies are potentially a viable treatment paradigm for PD.
BACKGROUND:Coenzyme Q10 (CoQ10) is a key mitochondrial electron carrier and a widely used dietary supplement with potential neurological benefits. However, the mechanisms underlying its effect in ameliorating memory deficits caused by cerebellar injury are not fully understood. In this study, we investigated the effects of long-term CoQ10 supplementation on working memory and the underlying mechanisms. METHODS:Network pharmacology analysis was used to identify genetic targets of CoQ10 in cerebellar injury-related cognitive impairment. Purkinje cell (PC)-specific Drp1-deficient mice (PC-Drp1-/-) were generated to model mitochondrial dysfunction. Behavioral performance was evaluated using the eight-arm radial maze. Mitochondrial structure and respiratory chain complex levels were evaluated by morphological and biochemical assays. Molecular targets of CoQ10 were identified using integrated drug-target engagement approaches, and their functional relevance was tested by viral vector-mediated overexpression. RESULTS:The PC-Drp1-/- mice displayed progressive working memory impairment and decreased PC density, accompanied by disrupted mitochondrial morphology and reduced activities of electron transport chain complexes III-V. Long-term CoQ10 treatment significantly reduced working memory errors and preserved PC numbers in PC-Drp1-/- mice. Target engagement analyses identified cytochrome c oxidase assembly factor 6 (Coa6) as a direct binding target of CoQ10. Viral vector-mediated overexpression of Coa6 in PCs partially recapitulated the CoQ10-associated improvements in respiratory chain complex levels and working memory, whereas Coa6 knockdown attenuated these benefits. CONCLUSIONS:CoQ10 directly interacts with Coa6 to enhance mitochondrial respiratory chain function and preserve PC integrity in the context of Drp1 deficiency. Our findings suggest a promising mechanistic pathway for CoQ10-based intervention in memory deficits associated with mitochondrial dysfunction.
