Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice

Niemann-Pick type C (NPC) disease is characterized by an accumulation of ch olesterol in most tissues and progressive neurodegeneration with the format ion of neurofibrillary tangles. Neurofibrillary tangles are composed of pai red helical filaments (PHF), a major component of which is the hyperphospho rylated tau. In this study we used NPC heterozygous and NPC homozygous mous e brains to investigate the molecular mechanism responsible for tauopathy i n NPC, Immunoblot analysis using anti-tau antibodies (Tau-1, PHF-1, AT-180, and AT-100) revealed site-specific phosphorylation of tau at Ser-396 and S er-404 in the brains of NPC homozygous mice. Mitogen-activated protein kina se, a potential serine kinase known to phosphorylate tau, was activated, wh ereas other serine kinases such as glycogen synthase kinase-3 beta and cycl in-dependent kinase 5 were inactive. Morphological examination demonstrated that a number of neurons the perikarya of which strongly immunostained wit h PHF-1, exhibited polymorphorous cytoplasmic inclusion bodies and multi-co ncentric lamellar-like bodies. Importantly, the accumulation of intracellul ar cholesterol in NPC mouse brains was determined to be a function of age. From these results we conclude that abnormal cholesterol metabolism due to the genetic mutation in NPC1 may be responsible for activation of the mitog en-activated protein kinase-signaling pathway and site-specific phosphoryla tion of tau in vivo, leading to tauopathy in NPC.