Notch signaling in the gliovascular unit of CADASIL and FAD

Abstract

ABSTRACT: The gliovascular unit (GVU) is a structural and functional unit of the central nervous system (CNS), composed of glial and vascular cells. Alzheimer's disease (AD) and vascular dementia (VaD), like Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), are the two most common forms of dementia. Furthermore, Colombia has the world's largest population of familial Alzheimer's disease (FAD). Interestingly, mutations in CADASIL (in Notch3) and FAD (PSEN1-E280A in γ-secretase) involve the Notch signaling pathway, which is critical for developing and maintaining vascular integrity, supporting the evidence of small vessel impairment in both diseases and suggesting a convergent phenomenon. The Grupo de Neurociencias de Antioquia (GNA) recently discovered a patient carrying the E280A mutation, but also a variant of the Apolipoprotein E protein (APOE3Ch patient), which conferred resistance to the development of FAD. APOE3Ch exhibited gliovascular protection, but the specific cells or the fully protective mechanism has yet to be studied. Considering the gliovascular alteration in CADASIL and FAD, its protection in APOE3Ch, and the Notch signaling involvement in these diseases, we set out to characterize Notch in the GVU cells in these conditions. To this end, we analyzed the frontal cortex of postmortem human patients by immunostaining, confocal microscopy, 3D analysis of the GVU, and western blotting. We found a novel convergent vascular alteration between CADASIL and FAD, specifically in mural cell deterioration and vascular inflammation caused by astrocytic and microglia reactivity surrounding vessels. However, there were differences between diseases. CADASIL was characterized by massive loss of mural cells and vascular inflammation mediated by astroglial and microglial reactivity, related to an ectopic distribution of N3ICD in microglial nuclei and loss in mural cells and astrocytes. On the other hand, FAD showed loss of mural cells in smaller caliber vessels and over coverage in larger vessels, and vascular inflammation mainly due to astroglial reactivity, related to an ectopic distribution of N3ICD in astrocytes, increased in somas, and loss in feet. These affections led to endothelial-mural-glial uncoupling related to Notch3 signaling alteration. The APOE3Ch-resistant case reverted the Notch-associated vascular alterations observed in FAD, suggesting that homeostatic Notch signaling in the GVU mediates vascular protection.