Supplementary Figure 10: GLUT1 deficiency leads to early cerebral microvascular degeneration, BBB breakdown, hypoperfusion, metabolic stress and accelerated accumulation of Aβ preceding neuronal functional and degenerative changes.

GLUT1 deficiency in endothelium leads to early cerebral microvascular degeneration (blue), limited BBB glucose uptake into the brain (blue), and disrupted Aβ metabolism (red) resulting in progressive BBB breakdown (blue), perfusion deficit (blue), potentially hypometabolic state (blue) and impaired vascular clearance of Aβ (red) via disruption of LRP1 (red). Ultimately, early microvascular degenerative changes resulting in accumulation of blood-borne toxins through a disrupted BBB, chronic perfusion and metabolic stress during limited glucose availability, as well as accumulation of neurotoxic Aβ species converge at the neuronal interface leading to neuronal dysfunction (blue), neuronal injury and neurodegeneration. Importantly, vascular damage precedes and helps drive neuronal changes as can be seen on the time scale.