ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2023
Cerebral Microvascular Injury Induced by Lag3-Dependent α-Synuclein Fibril Endocytosis Exacerbates Cognitive Impairment in a Mouse Model of α-Synucleinopathies.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 2 syntheses or guidelines pooled it, 17 citations in OpenAlex.
- The role and mechanisms of AMPK in neurovascular unit injury in Parkinson's disease.Frontiers in aging neuroscience · 2026Pooled it
- Association between herpes zoster and Parkinson's disease and dementia: a systematic review and meta-analysis.Frontiers in neurology · 2024Pooled it
- Neuroprotective effects of lixisenatide against propagation of α-synuclein pathology in Parkinson's disease.Neural regeneration research · 2026Article
- Microglial Lag3 Drives α-Synuclein-induced Neurotoxic Activated (A1) Astrocytes and Neurodegeneration.bioRxiv : the preprint server for biology · 2026Article
- Multiple sclerosis: molecular pathogenesis and therapeutic intervention.Signal transduction and targeted therapy · 2025Review
- Extracellular LCN2 Binding to 24p3R in Astrocytes Impedes α-Synuclein Endocytosis in Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- α-Synuclein Degradation in Brain Pericytes Is Mediated via Akt, ERK, and p38 MAPK Signaling Pathways.International journal of molecular sciences · 2025Article
- OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.Molecular neurodegeneration · 2025Review
- Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation.bioRxiv : the preprint server for biology · 2025Article
- Intrastriatal injection of alpha-synuclein preformed fibrils to rats results in L-DOPA reversible sensorimotor impairments and alterations in non-motor function.Frontiers in neuroscience · 2025Article
- Levodopa-induced dyskinesia: brain iron deposition as a new hypothesis.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2024Review
- Genetically modified E. Coli secreting melanin (E.melanin) activates the astrocytic PSAP-GPR37L1 pathway and mitigates the pathogenesis of Parkinson's disease.Journal of nanobiotechnology · 2024Article
- Abnormal Cerebrovascular Activity, Perfusion, and Glymphatic Clearance in Lewy Body Diseases.Movement disorders : official journal of the Movement Disorder Society · 2024Review
- Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.Nature communications · 2024Article
- The involvement of α-synucleinopathy in the disruption of microglial homeostasis contributes to the pathogenesis of Parkinson's disease.Cell communication and signaling : CCS · 2024Review
- Cerebral Microvascular Injury Induced by Lag3-Dependent α-Synuclein Fibril Endocytosis Exacerbates Cognitive Impairment in a Mouse Model of α-Synucleinopathies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
The pathological accumulation of α-synuclein (α-Syn) and the transmission of misfolded α-Syn underlie α-synucleinopathies. Increased plasma α-Syn levels are associated with cognitive impairment in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies, but it is still unknown whether the cognitive deficits in α-synucleinopathies have a common vascular pathological origin. Here, it is reported that combined injection of α-Syn preformed fibrils (PFFs) in the unilateral substantia nigra pars compacta, hippocampus, and cerebral cortex results in impaired spatial learning and memory abilities at 6 months post-injection and that this cognitive decline is related to cerebral microvascular injury. Moreover, insoluble α-Syn inclusions are found to form in primary mouse brain microvascular endothelial cells (BMVECs) through lymphocyte-activation gene 3 (Lag3)-dependent α-Syn PFFs endocytosis, causing poly(ADP-ribose)-driven cell death and reducing the expression of tight junction proteins in BMVECs. Knockout of Lag3 in vitro prevents α-Syn PFFs from entering BMVECs, thereby reducing the abovementioned response induced by α-Syn PFFs. Deletion of endothelial cell-specific Lag3 in vivo reverses the negative effects of α-Syn PFFs on cerebral microvessels and cognitive function. In short, this study reveals the effectiveness of targeting Lag3 to block the spread of α-Syn fibrils to endothelial cells in order to improve cognition.
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Registered trials
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