Alpha-Lipoic Acid Alleviates Cerebral Ischemic Injury-Induced Cognitive Impairment and Alzheimer’s Disease-Related Pathologies Through Modulation of GSK-3β in a Rat Model of Transient Middle Cerebral Artery Occlusion

Abstract Background There are two main types of dementia: Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID). Alpha-lipoic acid (ALA) has antioxidant and anti-inflammatory properties, and protects against cerebral ischemia-reperfusion (I/R) injury. We aimed to investigate the protective role of ALA in cerebral I/R injury-related cognitive impairment in a rat model of transient middle cerebral artery occlusion (tMCAO), which mimics VCID in humans. Methods After I/R injury, rats were treated with either an intraperitoneal injection of ALA (25 mg/kg) or vehicle. Infarct volume, brain edema, modified neurologic severity scores, and Y-maze test for cognitive impairment were assessed. In addition, activation of glycogen synthase kinase-3β (GSK-3β) and microglia, and expression of amyloid-β precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1), amyloid-β (Aβ), tau, and synaptophysin were measured 7 days after tMCAO. Results We found that administration of ALA after cerebral I/R injury reduced cerebral infarction, brain edema, and improved neurologic deficits and cognitive impairment. In parallel, ALA reduced the expression of APP, BACE1, Aβ, and phosphorylated tau in the hippocampus, down-regulated the activation of GSK-3β and microglia, and improved the integrity of neuronal synapses. Conclusion ALA alleviated the severity of cerebral I/R injury and AD-related pathologies, preserved neuronal integrity, and improved cognitive impairment by down-regulating the activation of GSK-3β and microglia.