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Project description:Multiomic profiling reveals pericyte and smooth muscle cell contributions to CADASIL pathology
2026-03-21 | PXD067619 | Pride
Project description:CADASIL, the most frequent and intensely studied monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3ECD) and the formation of protein deposits of insufficiently determined composition in the extracellular space of vessel walls. To advance our understanding of protein accumulation in CADASIL-affected tissue, we quantitatively determined the proteome of cerebral vessels isolated from patient and control autopsy samples (n = 6 for each group), obtaining 95 proteins with significantly increased abundance.
2018-08-03 | PXD009393 | Pride
Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts from a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed transcriptional changes and disease-associated cellular dysfunction, including activation of the NF-kB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient’s iPSCs. Importantly, the abnormal upregulation of NF-kB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the disease mechanisms of CADASIL and developing treatment strategies for this disease.
2018-12-31 | GSE124500 | GEO
Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease caused by NOTCH3 gene mutations, leading to vascular smooth muscle cell degeneration, arteriopathy, and subcortical ischemic infarcts. Many CADASIL patients, however, also develop cognitive impairment, indicating that neuronal functions are disturbed, but less is known about the cellular and molecular basis of these aspects in CADASIL. In this study, we used a humanized CADASIL mouse model harbouring the R182C mutation (R182C-TgN3), post-mortem human CADASIL brain sections with three different NOTCH3 gene mutations and primary human vascular smooth muscle cells harbouring the R133C NOTCH3 mutation as primary cellular models to characterise the neurovascular contribution to cognitive impairment. To specifically evaluate neuronal, mitochondrial and neurovascular function, we performed ex vivo electrophysiology, immunohistochemistry (confocal and iDISCO+ methods), western blotting, Seahorse assay, quantitative polymerase chain reaction (qPCR), and single-cell RNA sequencing. In CADASIL mice, hippocampal gamma oscillation patterns were impaired along with significant decreases in neuronal fiber length and aberrant neuronal morphology. The latter two phenotypes were also observed in post-mortem human brain tissue from CADASIL patients. Consistent with these findings, we noted significantly lower levels of mitochondrial respiratory complexes in the CADASIL mouse hippocampus, isolated mouse brain vessels and primary human vascular smooth muscle cells. Human vascular smooth muscle cells exhibited reduced oxygen consumption rates leading to reduced ATP production as well as decreased glycolytic capacity in conjunction with increased pro-inflammatory gene expression, suggesting a broader impact on cellular energy metabolism and a neuroinflammatory process. In the CADASIL mice, we also observed extensive accumulation of the NOTCH3 extracellular domain on hippocampal vessels. Light sheet imaging with iDISCO+ clearing demonstrated substantial vascular smooth muscle cell loss and reduced vessel density in the hippocampus at 9 months of age. Additionally, 3D imaging showed increased microglial attachment to vessels and enlargement of the size of the vessel-associated microglia in CADASIL mice. Single-cell RNA sequencing revealed a microglial subcluster expressing genes involved in mitochondria respiration and inflammation. Collectively, our results reveal that exacerbated vascular network damage may mediate cognitive decline observed in the later stages of CADASIL and highlight the critical role of the neurovascular unit. Our findings provide valuable insights into the underlying mechanisms of neuronal dysfunction and pave the way for future research and potential therapeutic strategies.
2026-02-06 | GSE300114 | GEO
Project description:NOTCH3 variants cause CADASIL (cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy), the most common monogenetic form of small vessel disease (SVD) and vascular dementia (VaD). Although CADASIL is well recognized clinically, the molecular mechanisms underlying its pathogenesis remain poorly understood, and no targeted therapies are currently available. NOTCH3 is predominantly expressed in vascular smooth muscle cells (VSMCs), which originate from distinct embryonic lineages. Using human induced pluripotent stem cell (iPSC) models, we generated origin-specific VSMCs and found that cerebral, but not peripheral, VSMC-mimics are selectively vulnerable to NOTCH3 variants. In this study, we focused on the neural crest-derived VSMCs and performed RNA-seq to compare gene expression profiles between wild-type and CADASIL patient iPSC-derived neural crest VSMCs.
2025-12-11 | E-MTAB-16303 | biostudies-arrayexpress
Project description:NOTCH3 mutation results in development of cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL), the most common monogenic small vessel disease. Up to date, specific treatment against CADASIL is scarce. Here, we report that both glymphatic influx and efflux are impaired in CADASIL mouse models (Notch3R170C), which impedes waste clearance and promotes brain senescence. In accordance, brain atrophy in CADASIL patients is associated with perivascular space enlargement, indicating that glymphatic impairment contributes to advanced brain senescence in CADASIL. The glymphatic malfunction in CADASIL is attributed to diminished AQP4 expression in astrocytic endfeet, which is the core mediator of glymphatic activity. Mechanistically, AQP4 expression is regulated by RUNX1-CMYB signaling whose activation is suppressed as a result of NOTCH3 mutation. Reinforcing AQP4 expression in astrocytes by AAV-based therapy resumes the glymphatic functions in CADASIL mice, which further prevents brain senescence. Therefore, we propose that to improve glymphatic function by reinforcing AQP4 expression is a promising therapeutic strategy in CADASIL. Senescence-associated Migrasomes (SAM) Promote Brain Ageing through Apoptosis Inhibitor of Macrophage (AIM) Aging is a major risk factor for various neurological disorders, including Alzheimer's disease (AD). During aging, senescent cells produce pro-aging factors that disseminate aging signals and reinforce the senescence process. Migrasomes, newly discovered organelles formed during cellular migration, detach from parent cells and mediate intercellular communication. In this study, we identify border-associated macrophages (BAMs) as the primary cells that acquire pro-senescent properties during brain aging, likely due to prolonged exposure to amyloid beta (A?). In pro-senescent BAMs, migrasome production is elevated, conveying pro-aging signals to neighboring cells. Mechanistically, the apoptosis inhibitor of macrophage (AIM) is packaged into migrasomes. Upon activation of CD16 in recipient cells, AIM protects them from apoptosis, thereby inducing senescence. Treatment with Tspan4-siRNA-encapsulated liposomes in 18-month-old mice suppresses migrasome production in pro-senescent BAMs, slows brain aging, and ameliorates cognitive deficits. Our findings suggest that migrasomes are potent carriers of pro-aging signals and represent a promising target for senomorphic therapy. Parenchymal border macrophages (PBMs) reside at the interface between the central nervous system and the periphery and are known to mediate the accessibility of the substances to the brain. Here, we report that amyloid-beta (A?) accumulates along brain blood vessels after stroke in both the ipsilateral and contralateral hemispheres. When PBMs were depleted, glymphatic drainage of A? was markedly reduced and this was accompanied by deterioration of cognitive function, highlighting a critical role for PBMs in post-stroke A? disposal. A possible mechanism relates to mesencephalic astrocyte-derived neurotrophic factor (MANF), which is known to impede glymphatic clearance of A?. MANF derived from PBMs suppressed astrocytic stress and maintained glymphatic drainage when supplemented into the cerebral spinal fluid. In the chronic phase of stroke, MANF production in PBMs was down-regulated and consequently, glymphatic impairments were exacerbated, which lead to on-going A? accumulation and cognitive decline. In summary, supplementation of MANF not only mitigates the adverse impacts of PBM depletion, but also exerts therapeutic effects that improve glymphatic system function. We thus propose that this represents a promising strategy to prevent post-stroke cognitive impairment.
2025-01-29 | GSE257560 | GEO
Project description: Not available
| S-EPMC9057602 | biostudies-literature
Project description:Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 (Notch3ECD) receptor are the two core features of CADASIL, the most common genetic cerebral small vessel disease. Although CADASIL is known to be caused by highly stereotyped dominant mutations in NOTCH3, the relationship between NOTCH3 receptor activity, Notch3ECD accumulation and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using novel histopathological and multiscale imaging modalities, we quantified previously undetectable CADASIL-driven focal arterial SMC loss in the central nervous system of mice expressing the archetypal Arg169Cys CADASIL mutation. Notably, we found more severe arterial pathology and greater Notch3ECD accumulation in transgenic model mice overexpressing the mutation on a homozygous wild-type Notch3 background (TgNotch3R169C) than in knock-in model Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. We further showed that wild-type Notch3ECD co-aggregated with mutant Notch3ECD and that elimination of one copy of wild-type Notch3 in TgNotch3R169C mice was sufficient to attenuate Notch3ECD accumulation and arterial pathology. Importantly, RNA sequencing revealed no substantial change in the expression of Notch3-regulated genes in TgNotch3R169C brain arteries. Collectively, our results provide compelling evidence that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, and not aberrant NOTCH3 signaling, is the key driver of arterial SMC loss in CADASIL, thus identifying NOTCH3-lowering approaches as candidate therapeutic strategies.
2024-04-17 | GSE242794 | GEO
Project description:We compared the gene expression in post-mortem brain specimen dissected from 2 CADASIL patients with samples from 5 non-affected controls in order to discover genes differentially expressed that could be involved in the development of neuronal damage in SVD. Samples form frontal cortex and white matter and occipital cortex and white matter were used.
2015-03-12 | E-MTAB-3395 | biostudies-arrayexpress
Project description: Not available
| S-EPMC9348820 | biostudies-literature