The Effect of Hippo Pathway Inhibitor Xmu‐mp‐1 on Cognitive Impairment in a Rat Model of Alzheimer’s Disease: Protection against Oxidative Stress, Tau Hyperphosphorylation, and Neurodegeneration

Abstract

AbstractBackgroundAlzheimer’s Disease (AD), the most common form of dementia, is a growing global health concern with unmet clinical therapeutics. AD can be attributed to amyloid beta aggregation and tau hyperphosphorylation‐induced oxidative stress and neurodegeneration in the brain. Previous studies have implicated a hyper‐activated Hippo signaling pathway with neuronal loss in neurodegenerative disorders, including AD. However, it is still unknown if suppressing the Hippo pathway can rescue neuronal death in AD.MethodIn this study, we investigated the cognitive impairment ameliorative effect of the novel Hippo signaling inhibitor, Xmu‐mp‐1, in a rat model of AD. Adult male Wistar rats were stereotaxically injected with a well‐known AD inducer Streptozotocin (STZ), to mimic AD‐like features. A pharmacological antagonist of Hippo signaling component MST1 called Xmu‐mp‐1 was administered intraperitoneally at a dose of 0.5mg/kg body weight for 14 days. Then the effect of Xmu‐mp‐1 on cognitive impairment was assessed using the Morris water maze test and novel object recognition test. Further, we did biochemical and histopathological studies to explore the effect of Xmu‐mp‐1 on several AD‐associated pathophysiological changes, including oxidative stress, tau hyperphosphorylation, and neurodegeneration.ResultXmu‐mp‐1 significantly improved the cognitive impairment of the AD rats in the Morris water maze test and the novel object recognition test (n = 7). Biochemical analysis of the brain hippocampal and cortical tissues revealed that Xmu‐mp‐1 also ameliorated the AD‐associated oxidative stress burden as the levels of anti‐oxidants (SOD, Catalase, GSH) significantly increased and the levels of oxidative stress biomarkers (protein carbonyl and lipid peroxidation) significantly reduced after Xmu‐mp‐1 treatment in the AD rats (n = 6). Moreover, the level of tau phosphorylation, a prime characteristic of AD, was also reduced following Xmu‐mp‐1 treatment (n = 3). Finally, neuronal death was also found to be rescued after Xmu‐mp‐1 treatment in AD rats (n = 3).ConclusionXmu‐mp‐1 exhibits a neuroprotective role against AD as it improves the cognitive impairment induced by STZ. Further mechanistic investigations into the neuroprotective role of Xmu‐mp‐1 revealed that Xmu‐mp‐1 provides protection from oxidative stress, tau hyperphosphorylation, and aberrant neurodegeneration under an AD background. Future studies can explore the therapeutic potential of Hippo signaling inhibition against AD in more detail.