Abstract
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.
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Akiyama H, Shin R-W, Uchida C, Kitamoto T, Uchida T (2005) Pin1 promotes production of Alzheimer’s amyloid beta from beta-cleaved amyloid precursor protein. Biochem Biophys Res Commun 336:521–529
Alvarez A, Toro R, Caceres A, Maccioni RB (1999) Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett 459:421–426
Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T (2001) Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J Biol Chem 276:40353–4036
Aplin AE, Gibb GM, Jacobsen JS, Gallo J-M, Anderton BH (1996) In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3β. J Neurochem 67:699–707
Arai H, Lee VM, Otvos L Jr, Greenberg BD, Lowery DE, Sharma SK, Schmidt ML, Trojanowski JQ (1990) Defined neurofilament, tau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques Proc Natl Acad Sci USA 87:2249–2253
Busciglio J, Lorenzo A, Yeh J, Yankner BA (1995) beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–888
Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446
Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P (1997) Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett 409:57–62
Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Aβ 42 fibrils. Science 293:1491–1495
Greenberg SG, Davies P, Schein JD, Binder LI (1992) Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. J Biol Chem 267:564–569
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274:99–102
Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T (2000) Neuron-specific phosphorylation of Alzheimer’s beta-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem 75:1085–1091
Imahori K, Uchida T (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J Biochem (Tokyo) 121:179–188
Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM (2001) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 158:555–562
Iwatsubo T, Yamaguchi H, Fujimuro M, Yokosawa H, Ihara Y, Trojanowski JQ, Lee VM (1996) Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am J Pathol 148:1517–1529
Kitamoto T, Ogomori K, Tateishi J, Prusiner SB (1987) Formic acid pretreatment enhances immunostaining of cerebral and systemic amyloids. Lab Invest 57:230–236
Kitamoto T, Mohri S, Ironside JW, Miyoshi I, Tanaka T, Kitamoto N, Itohara S, Kasai N, Katsuki M, Higuchi J, Muramoto T, Shin R-W (2002) Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions. Biochem Biophys Res Commun 294:280–286
Lang E, Szendrei GI, Lee VM-Y, Otvos L Jr (1992) Immunological and conformation characterization of a phosphorylated immunodominant epitope on the paired helical filaments found in Alzheimer’s disease. Biochem Biophys Res Commun 187:783–790
Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, Neve R, Ahlijanian MK, Tsai LH (2003) APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 163:83–95
Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491
Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235:1641–1644
Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Titani K, Ihara Y (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron 10:1151–1160
Murayama H, Shin R-W, Higuchi J, Shibuya S, Muramoto T, Kitamoto T (1999) Interaction of aluminum with PHFtau in Alzheimer’s disease neurofibrillary degeneration evidenced by desferrioxamine-assisted chelating autoclave method. Am J Pathol 155:877–885
Oishi M, Nairn AC, Czernik AJ, Lim GS, Isohara T, Gandy SE, Greengard P, Suzuki T (1997) The cytoplasmic domain of Alzheimer’s amyloid precursor protein is phosphorylated at Thr654, Ser655, and Thr668 in adult rat brain and cultured cells. Mol Med 3:111–123
Sato H, Hirata J, Furukawa M, Kuroda N, Shiraki H, Maeda Y, Okochi K (1991) Identification of the region including the epitope for a monoclonal antibody which can neutralize human parvovirus B19. J Virol 65:1667–1672
Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766
Shin R-W, Ogomori K, Kitamoto T, Tateishi J (1989) Increased tau accumulation in senile plaques as a hallmark in Alzheimer’s disease. Am J Pathol 134:1365–1371
Shin R-W, Iwaki T, Kitamoto T, Tateishi J (1991) Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer’s disease brain tissues. Lab Invest 64:693–702
Shin R-W, Iwaki T, Kitamoto T, Sato Y, Tateishi J (1992) Massive accumulation of modified tau and severe depletion of normal tau characterize the cerebral cortex and white matter of Alzheimer’s disease. Demonstration using the hydrated autoclaving method. Am J Pathol 140:937–945
Shin R-W, Bramblett GT, Lee VM-Y, Trojanowski JQ (1993) Alzheimer disease A68 proteins injected into rat brain induce codeposits of β-amyloid, ubiquitin, and α1-antichymotrypsin. Proc Natl Acad Sci USA 90:6825–6828
Shin R-W, Saido TC, Maeda M, Kitamoto T (2005) Novel α-secretase cleavage of Alzheimer’s amyloid beta precursor protein in the endoplasmic reticulum of COS7 cells. Neurosci Lett 376:14–19
Standen CL, Brownlees J, Grierson AJ, Kesavapany S, Lau K-F, McLoughlin DM, Miller CCJ (2001) Phosphorylation of thr (668) in the cytoplasmic domain of the Alzheimer’s disease amyloid precursor protein by stress-activated protein kinase 1b (Jun N-terminal kinase-3). J Neurochem 76:316–320
Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, KIshiguro K, Yamaguchi H (1998) Activation of tau protein kinase I/glycogen synthase kinase-3β by amyloid β peptide (25–35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 31:317–323
Tomita S, Ozaki T, Taru H, Oguchi S, Takeda S, Yagi Y, Sakiyama S, Kirino Y, Suzuki T (1999) Interaction of a neuron-specific protein containing PDZ domains with Alzheimer’s amyloid precursor protein. J Biol Chem 274:2243–2254
Weidemann A, Konig G, Bunke D, Fischer P, J. Salbaum M, C.L. Masters CL, Beyreuther K (1989) Identification, biogenesis, and localization of precursor of Alzheimer’s disease A4 amyloid protein. Cell 57:115–126
Acknowledgments
We thank Dr. J. Q. Trojanowski and V.M.-Y. Lee for providing the brain samples of the tau transgenic mice, Drs. P. Davies and S. Greenberg for providing PHF1, Dr. T. Suzuki for UT-18, and Dr. H. Sato for BE11. We also thank Ms. H. Kudo, Ms. K. Abe and Ms. A. Yamazaki for technical assistance. This study was supported by a grant from the Ministry of Health, Labor, and Welfare, Japan; and grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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Shin, RW., Ogino, K., Shimabuku, A. et al. 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. Acta Neuropathol 113, 627–636 (2007). https://doi.org/10.1007/s00401-007-0211-z
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DOI: https://doi.org/10.1007/s00401-007-0211-z