Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood‐brain barrier: Therapeutic avenues

Abstract Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high‐fat high‐sugar diet mimicking obesity‐induced type 2 diabetes mellitus (T2DM) in humans, we show that pro‐inflammatory mediators and altered immune responses damage the blood‐brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post‐mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS‐feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high‐fat high‐sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic‐disease‐associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.