Hyperglycemic Neurovasculature‐On‐A‐Chip to Study the Effect of SIRT1‐Targeted Therapy for the Type 3 Diabetes “Alzheimer's Disease”

Diabetes mellitus (DM) is closely related to Alzheimer's disease (AD), but individual cellular changes and the possibilities of recovery through molecular level regulation have not been investigated. Here, a neurovasculature‐on‐a‐chip (NV chip) model is presented in which the perfusable brain microvasculature is surrounded by the neurons. Under hyperglycemic conditions, the brain microvasculature shows disruption of barrier function and reduced expression of junctional markers. The neurons show Tau pathology and amyloid‐beta (Aß) accumulation. Endothelial cells and neurons in the NV chip show sirtuin 1 (SIRT1) downregulation under hyperglycemic conditions, suggesting SIRT1 as a key regulator of hyperglycemia‐induced AD. The recovery of glucose levels rescue SIRT1 expression, suggesting that this type of intervention may rescue the progression of hyperglycemia‐mediated AD. Furthermore, the short hairpin RNA (shRNA)‐, clustered regularly interspaced short palindromic repeats (CRISPR)‐, and pharmaceutics‐mediated regulation of SIRT1 regulate the pathophysiology of the brain endothelium and neurons at the functional and molecular levels. Here, a neurovasculature‐on‐a‐chip model in which a perfusable brain microvasculature is surrounded by the neurons under hyperglycemic or glucose‐recovery conditions is developed. The study elucidates the SIRT1‐mediated molecular mechanisms underlying the close relationship between diabetes and Alzheimer's disease. The study concludes that SIRT1 is a promising therapeutic target to rescue hyperglycemia‐induced AD.