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Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer’s, CADASIL, and Traumatic Brain Injury (ArcSwe data)

ABSTRACT: The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer’s disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the molecular responses in the vascular cells and microglia. Surprisingly, all vascular cell types remained transcriptomically normal across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering new insights into the predisposition for neurodegeneration following TBI.

ORGANISM(S): Mus musculus

PROVIDER: GSE318960 | GEO | 2026/04/30

REPOSITORIES: GEO

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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.

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.

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Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer’s, CADASIL, and Traumatic Brain Injury (ArcSwe data)

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