title: Val97Leu mutant presenilin-1 induces tau hyperphosphorylation and spatial memory deficit in mice and the underlying mechanisms.
abstract: Although the pathological role of presenilin-1 mutation in early onset familial Alzheimer's disease has been widely studied, few focused on how the presenilin-1 mutations result in memory impairment and tau hyperphosphorylation. In the present study, we expressed human Val97Leu mutant presenilin-1, which is reported in Chinese pedigrees by our group, in transgenic mice and found that the mutant presenilin-1 induced spatial memory deficit and tau hyperphosphorylation at PHF-1, pS199/202, pT231 and pS396 epitopes, but not at pS214 and pS422 epitopes. Pearson analysis showed that the memory deficit was only significantly correlated with tau phosphorylation level at PHF-1, pS199/202, pT231 and pS396 epitopes. Additionally, the hyperphosphorylated tau and tangle-like argentophilic structures were detected at CA3 and CA4, but not CA1, region of hippocampus, and we also found tangle-like structure and wizened degenerative neurons in frontal cortex. We demonstrated the tau hyperphosphorylation at the same epitopes in N2a cells expressing the mutant presenilin-1, which is caused by inhibition of phosphoinositol-3 kinase/Akt and activation of glycogen synthase kinase-3 specifically. Our data demonstrated that human Val97Leu mutant presenilin-1 causes spatial memory deficit in mice and increases tau phosphorylation level in glycogen synthase kinase-3-dependent manner.
authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Cheng
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.forename: Jianping
authors.initials: J
authors.lastname: Jia
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology; D006801:Humans; D007930:Leucine / Q000235:genetics; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology; D014633:Valine / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D007930:Leucine; D014633:Valine