Spatial Mapping of glial-vascular Interactions in CADASIL and Centenarians: Implications for Cerebrovascular Resilience

• Grant number: 25/14885-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: October 12, 2025
• End date: October 11, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mayana Zatz
• Grantee: Amanda Faria Assoni
• Supervisor: Dervis Ali Salih
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University College London (UCL), England
• Associated to the scholarship: 23/05836-1 - Identification of stroke protection mechanisms using vascularized organoids from healthy centenarians, BP.PD

Abstract

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the brain's most common monogenic small vessel disease, caused by mutations in the NOTCH3 gene. These mutations result in the accumulation of misfolded NOTCH3 extracellular domain (ECD) and the formation of granular osmiophilic material (GOM) in cerebral vessels, leading to vascular smooth muscle cell (vSMC) and pericyte degeneration. Despite extensive research on vascular pathology in CADASIL, the contributions of glial cells, particularly microglia and oligodendrocytes disease progression remain underexplored.Emerging evidence suggests that microglia, especially capillary-associated microglia (CAMs), play key roles in vascular homeostasis, blood-brain barrier (BBB) integrity, and neuroinflammatory responses. In CADASIL, perivascular microglia/macrophages exhibit increased pro-inflammatory activity, correlating with white matter lesion (WML) burden and cognitive decline. Likewise, oligodendrocytes, essential for myelin maintenance and neurovascular interaction, display early structural alterations in CADASIL mouse models, including myelin thinning and vesiculation, without outright cell loss. Notably, mature oligodendrocytes and their precursor cells (OPCs) directly engage with the vasculature, suggesting their vulnerability in the disease process.In contrast to this degenerative trajectory, some centenarians maintain preserved cognition into very old age, despite exposure to similar vascular risk factors. These individuals offer a unique model of cognitive resilience. Previous studies have shown that cognitively healthy centenarians exhibit lower levels of WMLs, as well as inherited protective traits. Interestingly, although neuronal numbers remain stable in advanced age, oligodendrocyte populations are significantly reduced, raising questions about the role of glial remodeling in successful aging.This project seeks to uncover how glial-vascular interactions differ between pathological (CADASIL) and resilient (centenarian) aging brains by applying high-resolution spatial transcriptomics to postmortem human brain tissue. We will map the spatial distribution and transcriptional profiles of CAMs and oligodendrocytes in three cohorts: CADASIL patients, cognitively intact centenarians, and matched controls. Through this approach, we aim to: (1) identify maladaptive glial phenotypes that contribute to microvascular degeneration in CADASIL; (2) detect protective signatures in centenarians that may underlie vascular resilience; and (3) explore cell-cell interactions and signaling pathways that mediate these phenotypes.Ultimately, this study will shed light on how the NOTCH3 pathway disrupts glial-vascular dynamics and how these effects differ from the preserved architecture seen in resilient aging. By uncovering molecular and spatial features of vulnerability and protection, this work has the potential to reveal new therapeutic targets for CADASIL and related small vessel diseases-conditions that currently lack effective treatment options.