Cart Attenuates Amyloid-β-induced Cognitive Deficits Through MAPK And AKT Signaling Pathway

BackgroundAlzheimer’s disease(AD), the most common cause of dementia in the elderly, is associated with two defining pathological lesions, including accumulation of senile plaques and neurofibrillary tangles. Amyloid-β protein (Aβ), the core of senile plaque, is one of the molecular pathological hallmarks of AD. Although more and more theories have been proposed to explain the mechanisms of Aβ-induced neurotoxicity, amyloid cascade hypothesis is still very popular. The accumulation of Aβ has been assumed to initiate a pathological cascade that results in oxidative stress, inflammation, synaptic abnormality and cognitive dysfunction. Furthermore, previous reports displayed that the intrahippocampus administration of Aβ1-42 peptide into rat brain induced AD symptoms.Cocaine and amphetamine regulated transcript (CART) peptide, which is widely expressed in the brain and peripheral nervous system, has been implicated in neuroprotecion, food intake, anxiety, drug addiction and depression. Previous research showed that CART level was decreased in the CSF of AD patients and CART can improve spatial learning ability. In our previous studies, CART has been shown to contribute to OGD-induced neuronal toxicity, apoptosis and inflammation as well as inhibit Aβ-induced neurotoxicy by Icariin.Objectivesthe aims of our study are:1) to investigate the effects of CART on the modulation of the mRNA and protein levels of Aβ metabolizing enzymes; 2) to explore the underlying mechanism of CART on Aβ clearance.MethodsKunming strain mice were treated with Aβ142 to establish AD models in vivo. Learning and memory impairment was tested by Morris water maze, the mRNA levels of Aβ Metabolizing enzymes were measured by real time PCR, and the protein levels of them were measured by western blot. In addition, western blot analysis was carried out to confirm that the possible mechanism of CART on Aβ clearance is linked to MAPK and AKT signaling pathway. And the levels of the metabolizing enzymes of Aβ in the neuron cells after treated with LY294002 were also measured by western blot.ResultsWe found that the escape latency were decreased and the crossing platform times were improved in the AD mice treatment of CART. In the cortex and the hippocampus of the AD mice, CART reduced the level of Aβ1-42. and inhibited the accumulation of AP plaques. CART improved the mRNA and protein levels of the Aβ degrading enzymes(IDE, NEP) and the levels of LRP-1. At the same time, CART decreased the mRNA level of the RAGE. Furthermore, CART could inhibit the MAPK signaling pathway and activate the AKT pathway. After treated with LY294002, the effect of CART on the enzymes was reversed.ConclusionsOur findings suggests that CART attenuates the learning and memory dysfunction in Aβ-induced AD models; reduces the accumulation of Aβ in the cortex and hippocampus of AD models; regulates the expression of Aβ degrading and transporting enzymes; induces the activation of Aβ1-42 suppressed AKT signaling pathway and decreases the activation of the JNK and p38.