Targeting blood brain barrier—Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats

Abstract Aims Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub‐lethal ischemic–reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long‐term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. Methods Female wild‐type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open‐field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro‐vasculature was examined using micro‐CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood–brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. Results RIC enhanced memory‐related protein expression and rescued depressive‐like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α‐secretase and attenuation of β‐secretase (BACE1) and γ‐ secretase and Aβ1‐42 and Aβ1‐40 levels as well. Conclusion Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.