Formation of Tau Inclusions in Knock-in Mice with Familial Alzheimer Disease (FAD) Mutation of Presenilin 1 (PS1)

Tetsuya Kimura,Takumi Akagi,Tsutomu Hashikawa,Tetsuya Fukuda,Miyuki Murayama,Masatoshi Takeda,Jung-Mi Park,Du-Hua Chui,Kentaro Tanemura,Tomohiro Miyasaka,Akihiko Takashima,Yuka Nakano,Yoshitaka Tatebayashi,Takashi Kudo

doi:10.1074/jbc.m509145200

Tetsuya Kimura, Takumi Akagi + Show 12 more

Open Access

https://doi.org/10.1074/jbc.m509145200

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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.

Highlights

Improper cleavage of amyloid precursor protein because of a presenilin 1 (PS1) mutation increases the production of A␤1–42 [5,6,7], a highly aggregative, neurotoxic species of A␤ that is longer than the less toxic A␤1–40
These findings indicate that heterozygous mPS1 mice, whose alleles most precisely reflect the genotype of humans bearing this mutation, exhibited phospho-tau accumulation with paired helical filaments (PHFs)-tau epitopes, whereas wPS1 mice of the same age showed no sign of tau accumulation
We demonstrated that the brains of mice harboring a PS1 mutation accumulated neurofibrillary tangles (NFTs)-like phospho-tau

Summary

Introduction

Improper cleavage of amyloid precursor protein because of a PS1 mutation increases the production of A␤1–42 [5,6,7], a highly aggregative, neurotoxic species of A␤ that is longer than the less toxic A␤1–40. Characterization of NFT-like Pathology in Mutant PS1 Mice—Fivemonth-old heterozygous mPS1 mice exhibited no pathological changes (Fig. 1A); in 7-month-old or older mice, we detected phosphotau accumulation (PS199) in neurons in the hippocampal region (Fig. 1B). These results suggest that mPS1 affects the cytoskeleton of hippocampal neurons and induces NFT-like accumulation of hyperphosphorylated tau.

Results

Conclusion