title: Formation of tau inclusions in knock-in mice with familial Alzheimer disease (FAD) mutation of presenilin 1 (PS1).
abstract: Mutations in the presenilin 1 (PS1) gene are responsible for the early onset of familial Alzheimer disease (FAD). Accumulating evidence shows that PS1 is involved in gamma-secretase activity and that FAD-associated mutations of PS1 commonly accelerate Abeta(1-42) production, which causes Alzheimer disease (AD). Recent studies suggest, however, that PS1 is involved not only in Abeta production but also in other processes that lead to neurodegeneration. To better understand the causes of neurodegeneration linked to the PS1 mutation, we analyzed the development of tau pathology, another key feature of AD, in PS1 knock-in mice. Hippocampal samples taken from FAD mutant (I213T) PS1 knock-in mice contained hyperphosphorylated tau that reacted with various phosphodependent tau antibodies and with Alz50, which recognizes the conformational change of PHF tau. Some neurons exhibited Congo red birefringence and Thioflavin T reactivity, both of which are histological criteria for neurofibrillary tangles (NFTs). Biochemical analysis of the samples revealed SDS-insoluble tau, which under electron microscopy examination, resembled tau fibrils. These results indicate that our mutant PS1 knock-in mice exhibited NFT-like tau pathology in the absence of Abeta deposition, suggesting that PS1 mutations contribute to the onset of AD not only by enhancing Abeta(1-42) production but by also accelerating the formation and accumulation of filamentous tau.
authors.affiliation: Laboratory for Alzheimer Disease and Neural Architecture, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tanemura
authors.forename: Du-Hua
authors.initials: DH
authors.lastname: Chui
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fukuda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Murayama
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Park
authors.forename: Takumi
authors.initials: T
authors.lastname: Akagi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tatebayashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miyasaka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D052160:Benzothiazoles; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D003224:Congo Red / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D053764:Presenilin-1; D011487:Protein Conformation; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C009462:thioflavin T; D012967:Sodium Dodecyl Sulfate; D003224:Congo Red; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse