Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer's disease and its transgenic models: a role to mediate interaction of Abeta and tau.
Abnormal accumulation of Abeta 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 Abeta 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 Abeta plaques in the brain. All Abeta plaques contain co-accumulations of pT668-ACD, but co-accumulation of tau appears in only a fraction of Abeta 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 Abeta 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 Abeta and tau.
Shin
Ryong-Woon
RW
Department of Neurological Science, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan. shin@mail.tains.tohoku.ac.jp
Ogino
Koichi
K
Shimabuku
Alfredo
A
Taki
Takao
T
Nakashima
Hanae
H
Ishihara
Takeshi
T
Kitamoto
Tetsuyuki
T
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology; D013912:Threonine / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D013912:Threonine