Dataset Information

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

ABSTRACT: Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.

SUBMITTER: Romay MC

PROVIDER: S-EPMC10786701 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

Romay Milagros C MC Knutsen Russell H RH Ma Feiyang F Mompeón Ana A Hernandez Gloria E GE Salvador Jocelynda J Mirkov Snezana S Batra Ayush A Sullivan David P DP Procissi Daniele D Buchanan Samuel S Kronquist Elise E Ferrante Elisa A EA Muller William A WA Walshon Jordain J Steffens Alicia A McCortney Kathleen K Horbinski Craig C Tournier-Lasserve Elisabeth E Sonabend Adam M AM Sorond Farzaneh A FA Wang Michael M MM Boehm Manfred M Kozel Beth A BA Iruela-Arispe M Luisa ML

The Journal of clinical investigation 20240116 2

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found ...[more]

PMID: 38015629

Similar Datasets

Project description:While most cases of vascular dementia represent complex interactions between host genetics and environmental factors, mendelian forms of vascular dementia also exist. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian disease characterized by progressive vascular deterioration, cognitive deficits, and strokes. Mutations in the NOTCH3 receptor underlies the pathologies in CADASIL. NOTCH3 is primarily expressed in vascular smooth muscle cell (vSMC) and its’ expression is critical for differentiation and functional integrity of arterial vSMCs, albeit through unclear mechanism(s). To elucidate the contribution of NOTCH3 in the maintenance of cerebral vascular architecture and function, we performed micro-computed tomography (micro-CT) on the brains of aged Notch3-deficient animals. Micro-CT assessment of the cerebral vasculature architecture showed significant abnormalities including severe vessel dilation and tortuosity (dolicoectasia) of the middle cerebral artery and its branches in the Notch3-/- compared to aged-match controls. To identify the molecular pathway from NOTCH3 dysregulation to the observed cerebral vascular dysfunction, we performed single-cell RNASeq on cerebral arteries isolated from young (4w) and old (104w) Notch3-/- animals. Evaluation of the vSMC-specific transcriptomes indicated significant loss of proteins associated with muscle contraction and increased extracellular matrix production in animals that lack NOTCH3. Using a combination of immunofluorescence microscopy and in vitro functional assays, we confirmed that continued expression of Notch3 is a critical requirement for maintenance of vSMC contractile function. Impaired contractility also affected flow of cerebrospinal fluid in the parenchyma of Notch3-/- . MRI and behavioral assessments were performed in the Notch3-/- animals to elucidate the relationship between impaired vascular contractility to cognitive function. Taken together these findings link the molecular dysfunction of NOTCH3 through its regulation of vascular contractility and cerebral vessel architecture to altered neurological function and clarify the molecular pathways to cellular pathology of Notch3 driven dementias.

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.

Dataset Information

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

Publications

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets