Prebiotic Lactulose Ameliorates the Cognitive Deficit in Alzheimer's Disease Mouse Model through Macroautophagy and Chaperone-Mediated Autophagy Pathways

Lactulose, as a prebiotic, can be utilized by human gut microbiota and stimulate their growth. Although microbiota modulation has become an emerging approach to manage many diseases and can be achieved by the administration of prebiotics, fewer investigations have been carried out on the therapeutic mechanism of lactulose. Two trehalose analogs, lactulose and melibiose, were identified as having a neuroprotective effect in polyglutamine and Parkinson disease models. In this study, we examined lactulose and melibiose in a mouse primary hippocampal neuronal culture under the toxicity of oligomeric A beta(23-35). Lactulose was further tested in vivo because its effective concentration is lower than that of melibiose. Lactulose and trehalose were applied individually to mice before a bilateral intrahippocampal CA1 injection of oligomeric A beta(23-35). The administration of lactulose and trehalose attenuated the short-term memory and the learning retrieval of Alzheimer's disease (AD) mice. From a pathological analysis, we found that the pretreatment of lactulose and trehalose decreased neuroinflammation and increased the levels of the autophagic pathways. These results suggest that the neuroprotective effects of both lactulose and trehalose are achieved through anti-inflammation and autophagy. In addition, lactulose was better than trehalose in the enhancement of the synaptic protein expression level in AD mice. Therefore, lactulose could potentially be developed into a preventive and/or therapeutic disaccharide for AD.

Automated summary

Lactulose and melibiose were found to alleviate cognitive impairments in AD mice through anti-inflammatory and autophagy mechanisms, with lactulose showing better enhancement of synaptic protein expression levels. These findings suggest that lactulose could potentially be developed as a preventive and/or therapeutic disaccharide for AD.