Remote Ischemic Conditioning Alleviates Alzheimer’s Disease Pathology in Female TgF344 Rats

Abstract

Abstract Alzheimer's disease (AD) has become a global public health crisis and research is urgently needed to explore strategies to prevent, and slow AD progression and improve cognitive function. Growing evidence suggests that blood vessels play a key role in physiological Aβ clearance, and blood biomarkers might hold promise for future diagnosis of AD. Remote ischemic conditioning (RIC), a noninvasive intervention by performing sub-lethal ischemic-reperfusion cycles on limbs, has been reported to exert beneficial effects after stroke, including increasing cerebral blood flow (CBF), anti-inflammation, and capillary remodeling. However, whether and how chronic RIC can prevent AD pathogenesis is largely unclear. In this study, female wild-type (WT) and TgF344 AD rats aged 3 months (young), 12 months (middle-age), and 19 months ± 3 weeks (old) were used to investigate the physical and pathological alterations of CBF and blood-brain barrier (BBB) in frontal parietal cortex. Furthermore, we selected middle-aged animals for RIC intervention five times each week for 4 weeks. Depression and cognitive function were measured using force swimming and Barnes maze tests. We also assessed the effects of aging and RIC intervention on BBB integrity; vascular-associated inflammatory factors VCAM1; dynamic alteration of astrocytes; production and clearance of Aβ; and changes in synaptic-associated proteins. The results revealed that CBF was initially high in young AD rats, followed by a significant decline in both middle- and old-age AD animals. Correspondingly, astrocytes presented reactive astrogliosis in young AD rats, followed by tightly vascular-wrapped hypertrophy in middle-aged AD rats, and degenerative or atrophic morphology in old-age AD rats. Likewise, BBB integrity was significantly impaired with aging in AD rats, as evidenced by loss of tight junction proteins ZO-1, and occludin. RIC intervention elevated CBF and protected capillary integrity, as evidenced by increased expression of TJ proteins and pericyte marker PDGFR1β, and decreases in VCAM1 protein. RIC also reversed degenerative morphology of astrocytes and upregulated A2 astrocyte phenotype markers PTX3, S100A10, and PAN marker GFAP, vimentin, while downregulating A1 astrocyte phenotype marker C3. Furthermore, RIC intervention significantly increased vascular endothelial glucose transporter (GLUT) 1 level and decreased BACE1 and Aβ1–42 levels. Finally, RIC intervention enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in middle-aged AD rats. These results demonstrated that BBB impairment and abnormal alteration of astrocytes occur at the early stage of AD. Chronic RIC intervention exerts vascular- and neuroprotective roles, suggesting that RIC may be a promising intervention targeting the BBB to prevent, and slow AD progression.