Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer's disease and its transgenic models: A role to mediate interaction of Aβ and tau

Ryong Woon Shin, Koichi Ogino, Alfredo Shimabuku, Takao Taki, Hanae Nakashima, Takeshi Ishihara, Tetsuyuki Kitamoto

研究成果: Article査読

48 被引用数 (Scopus)

抄録

Abnormal accumulation of Aβ and tau in senile plaques (SP) and neurofibrillary tangles (NFTs) is a key event in Alzheimer's disease (AD). Here, we show that T668-phosphorylated cytoplasmic domain of APP (pT668-ACD) accumulates Aβ and tau in AD and its transgenic models. Anti-pT668 immunostaining of AD brain sections with hydrated autoclave enhancement identified SP neurites and NFTs in which pT668-ACD colocalizes with tau. We produced and examined transgenic (Tg) mice that overexpress human APP695, harboring the double Swedish/London mutation, and develop age-dependently Aβ plaques in the brain. All Aβ plaques contain co-accumulations of pT668-ACD, but co-accumulation of tau appears in only a fraction of Aβ plaques in older animals. We also examined the established tau Tg mice that overexpress the smallest human brain tau isoform and develop neuronal accumulations of tau in older animals. Examination of the old tau Tg mice showed that neuronal cells affected by tau accumulation induce co-accumulation of pT668-ACD. We speculate that in AD brains, extracellular Aβ deposition is accompanied by intracellular accumulation of pT668-ACD, followed by tau accumulation in the SP with dystrophic neurites and that neuronal cells affected by tau accumulation induce co-accumulation of pT668-ACD in NFTs. Thus, pT668-ACD is likely to mediate pathological interaction between Aβ and tau.

本文言語English
ページ(範囲)627-636
ページ数10
ジャーナルActa neuropathologica
113
6
DOI
出版ステータスPublished - 2007 6月

ASJC Scopus subject areas

  • 病理学および法医学
  • 臨床神経学
  • 細胞および分子神経科学

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