Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer's disease

Abstract

Introduction: Dysfunction of the cerebral vasculature is considered one of the key components of Alzheimer's disease (AD), but the mechanisms affecting individual brain vessels are poorly understood.

Methods: Here, using in vivo two-photon microscopy in superficial cortical layers and ex vivo imaging across brain regions, we characterized blood-brain barrier (BBB) function and neurovascular coupling (NVC) at the level of individual brain vessels in adult female 5xFAD mice, an aggressive amyloid-β (Aβ) model of AD.

Results: We report a lack of abnormal increase in adsorptive-mediated transcytosis of albumin and preserved paracellular barrier for fibrinogen and small molecules despite an extensive load of Aβ. Likewise, the NVC responses to somatosensory stimulation were preserved at all regulatory segments of the microvasculature: penetrating arterioles, precapillary sphincters, and capillaries. Lastly, the Aβ plaques did not affect the density of capillary pericytes.

Conclusion: Our findings provide direct evidence of preserved microvascular function in the 5xFAD mice and highlight the critical dependence of the experimental outcomes on the choice of preclinical models of AD. We propose that the presence of parenchymal Aβ does not warrant BBB and NVC dysfunction and that the generalized view that microvascular impairment is inherent to Aβ aggregation may need to be revised.

Keywords: 5xFAD; Alzheimer’s disease; adsorptive-mediated transcytosis; blood-brain barrier; in vivo; neurovascular coupling; paracellular permeability; two-photon microscopy.