title: Increased phosphorylation of tau and synaptic protein loss in the aged transgenic mice expressing familiar Alzheimer's disease-linked presenilin 1 mutation.
abstract: Mutations in presenilin 1 (PS-1) are associated with most early-onset familiar Alzheimer's disease (AD). Previous studies have demonstrated that PS-1 mutations enhance the production of beta-amyloid (Aβ). In this study, we further examined the in vivo effects of PS-1 mutation on tau and synapse protein markers. The data showed that the phosphorylation of tau at Ser396, Ser404, Thr231 and Tau-1 (Ser198/199/202) epitopes was significantly increased in hippocampus of the aged (twenty-one and a half-month-old) transgenic mice expressing PS-1 (L235P) compared to that of the age-matched wild-type littermates (WTs). Concurrently, a significant decrease in the phosphorylation of glycogen synthase kinase (GSK)-3β at Ser9 was observed. The above changes were not observed in the young transgenic mice (6-8 months old). No significant changes in the levels of cyclin-dependent kinase (CDK)-5, its co-activator p35, and phosphorylation of protein phosphatase (PP)-2A catalytic subunit at Tyrosine 307 (Y307), a crucial site regulating the activity of PP-2A, were observed both in the young and aged transgenic mice compared to that of WTs. Furthermore, we also observed that the levels of presynaptic synaptophysin were significantly decreased but postsynaptic density protein (PSD)-95 were not significantly altered in hippocampus of the aged transgenic mice. No significant changes of synaptophysin or PSD-95 were observed in the brains of the young transgenic mice. Our data indicate that the L235P PS-1 mutation can induce Alzheimer-like tau hyperphosphorylation and synaptic protein loss, as well as increased production of Aβ.
authors.affiliation: Toxicology Laboratory, Shenzhen Centre for Disease Control and Prevention, 8 Longyuan Road, Nanshan District, 518055 Shenzhen, China. xifeiyang@gmail.com
authors.forename: Xifei
authors.initials: X
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Geng
authors.initials: G
authors.lastname: Li
authors.forename: Edward
authors.initials: E
authors.lastname: Yang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics*; D013569:Synapses / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D053764:Presenilin-1; D016875:tau Proteins