Summary
AD is a neurodegenerative disease characterized by the formation of neuronal inclusions, termed NFT, and extracellular amyloid deposits surrounded by dystrophic neuntes, collectively referred to as NP. NP are specific to AD, whereas NFT are found in many other neurodegenerative diseases. The purpose of this report is to present a hypothesis regarding the biochemical basis for these pathologic features of AD — neurodegeneration and NFT and NP formation.
Among the three AD pathologies, neurodegeneration is central to the disease. The reason for the premature death of neurons in AD brains is unknown. Because neuronal survival requires the combined effect of growth factors, it is possible that one or more growth factors are missing in the AD brain. Alternatively, the intracellular machinery responsible for the function of growth factors may be deficient in the disease. One form of machinery important for growth factor-mediated cell maintenance is the battery of protein kinases, in particular, PKC. PKC mediates many functions of nerve growth factor, the best-characterized neurotrophic factor. Both the kinases, including PKC, and the phosphorylation levels are altered in AD brains, whereas levels of nerve growth factor are not.
There are questions to be answered. Is aberrant phosphorylation in AD specific to this disease? Is aberrant phosphorylation intrinsic to AD or secondary to neurodegeneration? Is PKC reduction relevant to NFT and NP formation? Why is phosphorylation aberrant in AD?
The abnormality in phosphorylation may be related to the expression of some biochemical characteristics that correlate with NFT formation. Furthermore, phosphorylation may be involved in the regulation of the processing of ABPP, which constitutes a major portion of the NP core. Conversely it is possible that ABPP is involved in the regulation of phosphorylation in neurons. Because ABPP is aberrantly processed in AD brain, this protein may be a candidate as the cause of abnormal phosphorylation and eventual neurodegeneration in AD.
This work was supported by grants from the Alzheimer’s Disease and Related Disorders Association, the McKnight Foundation, the California State Department of Health Services, the Sandoz Foundation for Gerontological Research, and the National Institutes of Health (AG 05386, AG 05131, and AG 08205). D.S.I, is the recipient of a Pathological Training Grant (NS07078–12).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of normally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99
Baudier J, Cole RD (1987) Phosphorylation of tau proteins to a state like that in Alzheimer’s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J Biol Chem 262:17577–17583
Baudier J, Lee S-H, Cole RD (1987) Separation of the different microtubule-associated tau protein species from bovine brain and their mode II phosphorylation by Ca2+/phospholipid-dependent protein kinase C J Biol Chem 262:17584–17590
Birecree E, Whetsell WO, Stoscheck C, King LE, Nanney LA (1988) Immunoreactive epidermal growth factor receptors in neuritic plaques from patients with Alzheimer’s disease. J Neuropathol Exp Neural 47:549–560
Blass JP, Zemcov A (1984) Alzheimer’s disease: a metabolic systems degeneration? Neurochem Pathol 2:103–114
Brion JP, van den Bosch de Aguilar P, Flament-Durand J (1985) Senile dementia of the Alzheimer type: morphological and immunocytochemical studies. In: Traber J, Gispen WH (eds) Senile dementia of the Alzheimer type. Springer, Berlin Heidelberg New York, pp 164–174 (Advances in applied neurological sciences, vol 2)
Clark AW, Krekoski CA, Parhad IM, Liston D, Julien J-P, Hoar DI (1989) Altered expression of genes for amyloid and cytoskeletal proteins in Alzheimer cortex. Ann Neurol 25:331–339
Cleveland DW, Hwo S-Y, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227–247
Cole G, Dobkins KR, Hansen LA, Terry RD, Saitoh T (1988) Decreased levels of protein kinase C in Alzheimer brain. Brain Res 452:165–174
Cole C, Masliah E, Terry RD, Huyhn TV, DeTeresa R, Saitoh T (1989) An antiserum against amyloid β-protein precursor detects a unique peptide in Alzheimer’s brain. Neurosci Lett 100:340–346
Diaz-Nido J, Serrano L, Méndez E, Avila J (1988) A casein kinase II-related activity is involved in phosphorylation of microtubule-associated protein MAP-IB during neuroblastoma cell differentiation. J Cell Biol 106:2057–2065
Gandy S, Czernik AJ, Greengard P (1988) Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II. Proc Natl Acad Sci USA 85:6218–6221
Goedert M, Fine A, Hunt SP, Ullrich A (1986) Nerve growth factor mRNA in peripheral and central rat tissues and in the human central nervous system: lesion effects in the rat brain and levels in Alzheimer’s disease. Mol Brain Res 1:85–92
Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 85:4051–4055
Greengard P (1978) Phosphorylated proteins as physiological effectors. Science 119:146–152
Grundke-Iqbal I, Iqbal K, Tung Y-C, Quinlan M, Wiśniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917
Hoshi M, Nishida E, Miyata Y, Sakai H, Miyoshi T, Ogawara H, Akiyama T (1987) Protein kinase C phosphorylates tau and induces its functional alterations. FEBS Lett 217:237–241
Huyhn TV, Cole G, Katzman R, Huang K-P, Saitoh T (1989) Reduced MT 79,000 protein phosphorylation and PK-C immunoreactivity in AD fibroblasts. Arch Neurol, in press
Hyman BT, Van Hoesen GW, Wolozin BL, Davies P, Kromer LJ, Damasio AR (1988) Alz-50 antibody recognizes Alzheimer-related neuronal charges. Ann Neurol 23:371–379
Ihara Y, Nukina N, Miura R, Ogawara M (1986) Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J Biochem 99:1807–1810
Iimoto DS, Masliah E, DeTeresa R, Terry RD, Saitoh Τ (1989) Aberrant casein kinase II in Alzheimer’s disease. Submitted
Iimoto DS, Saitoh Τ (1988) Altered casein kinase activity in Alzheimer brain. Soc Neurosci Abstr 14:1085
Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA, Wen GY, Shaikh SS, Wisniewski HM, Alafuzoff I, Winblad В (1986) Defective brain microtubule assembly in Alzheimer’s disease. Lancet 11:421–426
Ishiguro K, Ihara Y, Uchida T, Imahori К (1988) A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau. J Biochem 104:319–321
Kessler JA (1987) Deficiency of a cholinergic differentiating factor in fibroblasts of patients with Alzheimer’s disease. Ann Neurol 21:95–98
Klarlund JK, Czech MP (1988) Insulin-like growth factor I and insulin rapidly increase casein kinase II activity in BALC/C 3T3 fibroblasts. J Biol Chem 263:15872–15875
Kochhar A, Saitoh T, Zivin JA (1989) Reduced protein kinase С activity in ischemic spinal cord. J Neurochem 53:946–952
Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (τ) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 83:4044–4048
Kosik KS, Orecchio LD, Binder L, Trojanowski JQ, Lee VM-Y, Lee G (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1:817–825
Krebs EG, Beavo JA (1979) Phosphorylation-dephosphorylation of enzymes. Annu Rev Biochem 48:923–959
Ksiezak-Reding H, Davies P, Yen S-H (1988) Alz-50, a monoclonal antibody to Alzheimer’s disease antigen, cross-reacts with τ proteins from bovine and normal human brain. J Biol Chem 263:7943–7947
Li JC, Kaminskas E (1985) Deficient repair of DNA lesions in Alzheimer’s disease fibroblasts. Biochem Biophys Res Commun 129:733–738
Lindwall G, Cole RD (1984) The purification of tau protein and the occurrence of two phosphorylation states of tau in brain. J Biol Chem 59:12241–12245
Mattson MP, Guthrie PB, Kater SB (1988) Intracellular messengers in the generation and degeneration of hippocampal neuroarchitecture. J Neurol Res 21:447–464
Meier-Ruge W, Ivangoff P, Reichlmeier К (1984) Neurochemical enzyme changes in Alzheimer’s and Pick’s disease. Arch Gerontol Geriat 3:61–65
Neve RL, Finch EA, Dawes LR (1988) Expression of the Alzheimer amyloid precursor gene transcripts in the human brain. Neuron 1:669–677
Nishizuka Y (1988) The molecular heterogeneity of protein kinase С and its implications for cellular regulation. Nature 334:661–665
Nukina N, Kosik KS, Selkoe DJ (1988) The monoclonal antibody, Alz-50, recognizes tau proteins in Alzheimer’s disease brain. Neurosci Lett 87:240–246
Peterson С, Goldman JE (1986) Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci USA 83:2758–2762
Peterson C, Ratan RR, Shelanski ML, Goldman JE (1986) Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci USA 83:7999–8001
Saitoh T, Cole G, Huynh TV (1989) Aberrant protein kinase С cascades in Alzheimer’s disease. In: Lauder J, Privat A, Giacobini E, Timiras PS, Vernadakis A (eds) Molecular aspects of development and aging of the nervous system. Plenum, New York, in press
Saitoh T, Dobkins KR (1986a) In vitro phosphorylation of a MT 60,000 protein is elevated in Alzheimer brain. Proc Natl Acad Sci USA 83:9764–9767
Saitoh T, Dobkins KR (1986b) Protein kinase С in human brain and its inhibition by calmodulin. Brain Res 379:196–199
Saitoh T, Hansen LA, Dobkins KR, Terry RD (1988) Increased Mr 60,000 protein phosphorylation is correlated with neocortical neurofibrillary tangles in Alzheimer’s disease. J Neuropathol Exp Neurol 47:1–8
Schubert D, LaCorbiere M, Saitoh T, Cole G (1989) Characterization of an amyloid β-precursor protein that binds heparin and contains tyrosine sulfate. Proc Natl Acad Sci USA 86:2066–2069
Schubert D, Schroeder R, LaCorbiere M, Saitoh T, Cole G (1988) Amyloid β protein precursor is possibly a heparan sulfate proteoglycan core protein. Science 241:223–226
Serrano L, Diaz-Nido J, Wandosell F, Avila J (1987) Tubulin phosphorylation by casein kinase II is similar to that found in vivo. J Cell Biol 105:1731–1739
Snow AD, Mar H, Nochlin D, Kinata K, Kato M, Suzuki S, Hassell J, Wight TN (1988) The presence of heparin sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer’s disease. Am J Pathol 133:456–463
Sternberger NH, Sternberger LA, Ulrich J (1985) Aberrant neurofilament phosphorylation in Alzheimer’s disease. Proc Natl Acad Sci USA 82:4274–4276
Tanaka S, Nakamura S, Uéda К, Kameyama M, Shiojiri S, Takahashi Y, Kitaguchi Ν, Ito H (1988) Three types of amyloid protein precursor mRNA in human brain: their differential expression in Alzheimer’s disease. Biochem Biophys Res Commun 157:472–479
Terry RD, Katzman R (1983) Senile dementia of the Alzheimer type. Ann Neurol 14:497–506
Uéda K, Cole G, Sundsmo M, Katzman R, Saitoh T (1989) Decreased adhesiveness of Alzheimer fibroblast: is β-protein precursor involved? Ann Neurol 25:246–251
Whitson JS, Selkoe DJ, Cotman CW (1989) Amyloid β-protein enhances the survival of hip-pocampal neurons in vitro. Science 243:1488–1490
Wood JG, Mirra SS, Pollock NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (τ). Proc Natl Acad Sci USA 83:4040–4043
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1989 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Saitoh, T., Iimoto, D.S. (1989). Altered Protein Kinase and Amyloid ß-Protein Precursor in Alzheimer’s Disease: Which Comes First?. In: Boller, F., Katzman, R., Rascol, A., Signoret, JL., Christen, Y. (eds) Biological Markers of Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46690-8_10
Download citation
DOI: https://doi.org/10.1007/978-3-642-46690-8_10
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-46692-2
Online ISBN: 978-3-642-46690-8
eBook Packages: Springer Book Archive