Decreased Estradiol Release from Astrocytes Contributes to the Neurodegeneration in a Mouse Model of Niemann-Pick Disease Type C

Niemann-Pick disease type C; astrocyte; estradiol; neuron-glia interaction; neurodegenerative disease Niemann-Pick disease type C (NPC) is a deadly neurodege-nerative disease often caused by mutation in a gene called NPC1, which results in the accumulation of unesterified cho-lesterol and glycosphingolipids in the endosomal–lysosomal system. Most studies on the mechanisms of neurodegenera-tion in NPC have focused on neurons. However, the possibil-ity also exists that NPC1 affects neuronal functions indirectly by acting on other cells that are intimately interacting with neurons. In this study, using a heterotypic neuron-glia cocul-ture system, we found that wild-type neurons cultured on a layer of NPC12/2 astrocytes showed decreased neurite growth compared with those cultured on wild-type astrocytes. RT-PCR and immunohistochemical assessments showed sig-nificantly lower expression of neurosteroid enzymes and StAR (steroidogenic acute regulatory protein) in NPC12/2 astrocyte cultures than in wild-type cultures. Furthermore, a reduced level of estradiol was measured from both astrocyte culture medium and whole brains from NPC12/2 mice. Administration of 17b-estradiol to neonatal NPC12/2 mice significantly delayed the onset of neurological symptoms, increased Purkinje cell survival, and extended the animals’ life span. Our findings suggest that astrocyte dysfunction contributes to the neurodegeneration of NPC and estradiol treatment may be useful in ameliorating progression of the disease. VC 2007 Wiley-Liss, Inc