The Effect And Mechanisms Of Progranulin On Alzheimer's Disease

Alzheimer's disease(AD)is a central nervous system degenerative disease characterized by progressive cognitive impairment and memory impairment.At present,A? is considered to be a direct cause of Alzheimer's disease.In the AD brain,the imbalance between A? generation and clearance is an early event that leads to long-term accumulation and aggregation of A?,which finally results in amyloid plaque deposition and neurotoxicity.Progranulin(PGRN)is a secreted glycosylated protein expressed in various organs and tissues.In the brain,progranulin is secreted by neurons and microglia,plays an important role in neuroinflammation and neuronal survival.Previous works reported that the deficiency of progranulin accelerates ?-amyloid(A?)accumulation in AD transgenic mouse brains and overexpression of progranulin could restrain disease progression.However,the mechanisms of progranulin in protecting against A? deposition and interactional relations between the progranulin and AD pathology remain unclear.To answer these questions,we used 5xFAD AD mouse model and cultured cells.We found that the content of progranulin in the brain of 3-month-old 5xFAD mice was increased,while,in the brains of 6-month-old and 10-month-old 5xFAD mice decreased,compared with WT mice.Over-expression of the mutant gene(APP-swe mutation)or treatment with A?42 oligomers could reduce progranulin content in N2a cells in vitro.On the other hand,we found that intracerebral administration of recombinant progranulin can reduce the deposition of A? plaques in the hippocampus of 5xFAD mice.Furthermore,we found that progranulin can decrease the expression of ?-secretase(BACE1)and enhances the phagocytic capacity of microglia.These results partially reveal the role of progranulin in the pathogenesis of Alzheimer's disease.During the pathological process of Alzheimer's disease,the expression of progranulin is reduced,and progranulin supplementation can attenuates Alzheimer's disease pathology.Our data suggest that progranulin protects against A? deposition at least in two ways,one is reducing the production of A?through inhibiting BACE1 expression,and another is promoting the clearance of A?via enhancing microglial phagocytosis.Our research uncovers part of the mechanism of progranulin in Alzheimer's disease pathology,and also provide new thinkings for the study of progranulin in Alzheimer's disease.