TY - JOUR
T1 - Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer's disease and its transgenic models
T2 - A role to mediate interaction of Aβ and tau
AU - Shin, Ryong Woon
AU - Ogino, Koichi
AU - Shimabuku, Alfredo
AU - Taki, Takao
AU - Nakashima, Hanae
AU - Ishihara, Takeshi
AU - Kitamoto, Tetsuyuki
PY - 2007/6
Y1 - 2007/6
N2 - 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.
AB - 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.
KW - APP
KW - Alzheimer's disease
KW - Aβ
KW - Tau
KW - Transgenic mice
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UR - http://www.scopus.com/inward/citedby.url?scp=34249880509&partnerID=8YFLogxK
U2 - 10.1007/s00401-007-0211-z
DO - 10.1007/s00401-007-0211-z
M3 - Article
C2 - 17431643
AN - SCOPUS:34249880509
VL - 113
SP - 627
EP - 636
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 6
ER -