Study On The Effect And Mechanism Of DhHP-6 Against Alzheimer's Disease

Alzheimer's disease?AD?,commonly known as dementia,is regarded as a typical neurodegenerative brain disease.There are approximately 47 million people with senile dementia globally.AD is characterized by the deposition of amyloid,neurofibrillary tangles?NFT?,loss of neurons,progressive deterioration of memory and cognition,and a gradual worsening of behavioral disturbances,which threatens human health seriously,also brings heavy burden to the patients,family and society in worldwide.Current studies have shown that proteolytic cleavage of the amyloid?precursor protein?A?PP?by?-and?-secretase could lead to the production and accumulation of A?₁–₄₀0 and A?₁–₄₂.?-amyloid as a kind of pathogenic factors will self-assemble into various amyloid species,which leads to the imbalance of redox homeostasis,neuron damage and cognitive impairment.Moreover,excessive free radicals promote the wrong cleavage of APP and A?plaque deposition even further.These two factors promote each other and form a vicious circle.Therefore,regulating the redox homeostasis in vivo and reducing A?deposition are important directions and hot topic of anti-AD drug researches.Deuterohemin-AlaHisThrValGluLys?DhHP-6?as a novel peroxidase mimetic peptide,is designed on the natural microperoxidase-11?MP-11?with heme-porphyrin,and it has strong free radical scavenging activity.Furthermore,it has better water solubility,stability and is easy to synthesize.Previous studies showed that DhHP-6 could extend the lifespan of C.elegans?Bristol N2?for 19.3%,protect it against heat-and paraquat-induced damage.Therefore,it is crucial to explore the mechanism of DhHP-6 against Alzheimer's disease based on free radical damage hypothesis.In this paper,we chose A?_1-42 transgenic nematode as AD model to study the protective effect of DhHP-6 against Alzheimer's disease.Results showed that DhHP-6 prolonged the lifespan,delayed the paralysis,and reduced the deposition of A?plaque significantly in A?_1-42 transgenic C.elegans?CL4176?.More importantly,we found DhHP-6 played an important role in regulating the expression of mitochondria-associated genes based on transcriptomics analysis and realtime PCR assay.Further,we selected APPswe/PS1dE9 double transgenic AD mice as a model to explore the improvement effect of DhHP-6 on cognitive ability and brain lesion.Results indicated that DhHP-6significantly improved the spatial learning ability and short-term memory ability of AD mice by Morris water maze and Y-maze,and significantly improved the cognitive level,social ability,new object recognition,approach-avoidance behavior,spatial exploration ability and neurotrosis in the hippocampus of AD mice through nesting,three-chamber social,new object recognition,step-through task,open field and autonomic activities experiments.More importantly,DhHP-6inhibited the cell apoptosis by reducing the A?plaque deposition in brain,and reduced the levels of soluble A?_1-40 and A?_1-42 in brain tissue and plasma.Besides,it also improved the morphology of microglia and astrocytes,reduced inflammatory factors,increased the activity of antioxidant enzyme and improved the morphology of mitochondria.In addition,DhHP-6 was safe and nontoxic for the viscera of AD mice.To further explore the mechanism of DhHP-6 on AD,we constructed APP_595/596-HT22transfection nerve cell based on mouse hippocampal neuron cell line HT22.Results showed that DhHP-6 had neuroprotective effect on the overexpression of APP induced cytotoxicity,and which significantly improved the activity of antioxidant enzymes and reduced the level of extracellular inflammatory factors in APP_595/596-HT22 cell.Moreover,DhHP-6 exerted antioxidant function and effect through Nrf-2/HO-1 signaling pathway in APP_595/596-HT22 cell by western blot assay.In summary,DhHP-6 exerted antioxidant and neuroprotective effect on AD through the Nrf-2/HO-1 signaling pathway in vivo,which could provide new ideas and set the foundation for the development of new drugs against Alzheimer's disease.