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Linking trajectories of cerebrovascular remodeling and dysfunction to cross-species brain vessel transcriptome in Alzheimer’s disease

ABSTRACT: Growing evidence implicates dysfunctional brain vasculature occurring early in Alzheimer’s disease (AD) progression. Few studies have attempted to bridge transcriptomic signatures with early neuroimaging observations of vascular abnormalities. We leveraged longitudinal in vivo imaging of the cerebrovascular tree in APP/PS1 mice to identify when vascular abnormalities emerge, followed by bulk RNA-seq of isolated brain vessels at this time point. At 9–11 months of age, AD mice exhibited microvascular remodeling and dysfunction, including increased tortuosity, decreased capillary blood flow and reduced vascular density. Enriched gene pathways highlighted increased neuroinflammation, dysfunctional angiogenesis, and deficits in actin-mediated muscle contractility. Mapping transcriptional changes to a mouse vascular atlas implicated endothelial cells and microglia in impaired angiogenesis, while mural cells showed actin-filament and ion channel deficits. Mapping to a human vascular atlas identified translational targets to alleviate actin-mediated contractility deficits. Our integrated framework advances cerebrovascular biomarker understanding and informs early-stage AD therapeutic targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE291921 | GEO | 2026/03/13

REPOSITORIES: GEO

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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.

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Linking trajectories of cerebrovascular remodeling and dysfunction to cross-species brain vessel transcriptome in Alzheimer’s disease

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