Neurobiological pathways to Alzheimer's disease: Amyloid-beta, TAU protein or both?

Paula, Vanessa de Jesus R. de; Guimarães, Fabiana Meira; Diniz, Breno Satler; Forlenza, Orestes Vicente

doi:10.1590/S1980-57642009DN30300003

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-b₄₂ peptide (Ab₄₂). Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated TAU protein. In this article, we review the major hypotheses concerning the physiopathology of AD, focusing on the b-amyloid cascade as primary events (supported by the "baptists") and cytoskeletal abnormalities secondary to the hyperphosphorylation of protein TAU (as advocated by the "Tauists"). We further provide an integrative view of the physiopathology of AD.

Key words:
TAU protein; amyloid precursor protein; beta amyloid; Alzheimer's disease.

Resumo

A doença de Alzheimer (DA) é uma desordem neurodegenerativa progressiva que cursa comprometimento da memória e outras funções cognitivas, alterações comportamentais, psíquicas e da personalidade. Os achados neuropatológicos característicos da DA são as placas neuríticas (senis) e os emaranhados neurofibrilares, também ocorrendo distrofia de neuritos, gliose e perda neuronal. As placas neuríticas são lesões extracelulares que têm no peptídeo beta-amilóide (Ab₄₂) seu principal constituinte. Os emaranhados neurofibrilares são lesões intraneuronais compostas por agregados de proteína TAU em estado hiperfosforilado. Neste artigo de revisão, apresentamos as principais hipóteses relacionadas à fisiopatologia da DA, com foco na cascata do amilóide como evento inicial (hipótese preconizada pelos "baptistas") e nas alterações do citoesqueleto neuronal, decorrentes da fosforilação anormal da TAU (conforme proposto pelos "tauístas"). Os achados são discutidos numa leitura integrada desses dois mecanismos fisiopatológicos.

Palavras-chave:
TAU; proteína precursora do amilóide; beta-amilóide; doença de Alzheimer.

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References

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Herrera E Jr, Caramelli P, Silveira AS, Nitrini R. Epidemiologic survey of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord 2002;16:103-108.
²
Nitrini R, Caramelli P, Herrera E Jr, et al. Incidence of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord 2004;18:241-246.
³
Hestad K, Kveberg B, Engedal K. Low blood pressure is a better predictor of cognitive deficits than the apolipoprotein e4 allele in the oldest old. Acta Neurol Scand 2005;111:323-328.
⁴
Ravona SR, Davidson M, Noy S. The role of cardiovascular risk factors in Alzheimer's disease. CNS Spectr 2003;8:824-833.
⁵
Boeras DI, Granic A, Padmanabhan J, Crespo NC, Rojiani AM, Potter H. Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol Aging 2008;29:319-328.
⁶
Castellani RJ, Lee HG, Zhu XW, Nunomura A, Perry G, Smith MA. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic, Acta Neuropathol 2006;111: 503-509.
⁷
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-259.
⁸
Di Luca M, Colciaghi F, Pastorino L, Borroni B, Padovani A, Cattabeni F. Platelets as a peripheral district where to study pathogenetic mechanisms of alzheimer disease: the case of amyloid precursor protein. Eur J Pharmacol 2000;405:277-283.
⁹
Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1994;57: 419-425.
¹⁰
Korczyn AD. The amyloid cascade hypothesis. Alzheimers Dement 2008;4:176-178.
¹¹
Kontush A. Apolipoprotein Abeta: black sheep in a good family. Brain Pathol 2004;14:433-447.
¹²
Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L. Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS ONE 2008;23:2718.
¹³
Rhein V, Eckert A. Effects of Alzheimer's amyloid-beta and tau protein on mitochondrial function: role of glucose metabolism and insulin signaling. Arch Physiol Biochem. 2007; 113:131-141.
¹⁴
Oide T, Kinoshita T, Arima K. Regression stage senile plaques in the natural course of Alzheimer's disease. Neuropathol Appl Neurobiol 2006;32:539-556.
¹⁵
Vetrivel KS, Thinakaran G. Amyloidogenic processing of b-amyloid precursor protein in intracellular compartments. Neurology 2006;66(2 Suppl 1):S69-S73.
¹⁶
Kunjathoor VV, Tseng AA, Medeiros LA, Khan T, Moore KJ. b-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins. J Neuroinflammation 2004;16:23.
¹⁷
Kosik KS. The molecular and cellular biology for tau. Brain Path 1993;3:39-43.
¹⁸
Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 1984;259:5301-5305.
¹⁹
Cleveland DW, Hoffman PN. Neuronal and glial cytoskeletons. Curr Opin Neurobiol 1991;1:346-353.
²⁰
Lovestone S, Anderton B. Cytoskeletal abnormalities in Alzheimer's disease. Curr Opin Neurol Neurosurg 1992;5:883-888.
²¹
Trojanowski JQ, Lee VM. Paired helical filament tau in Alzheimer's disease. The kinase connection: neurobiology of Alzheimer's disease. Am J Pathol 1994;144:449-453.
²²
Lovestone S, Reynolds CH, Latimer D, et al. Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 1994;4:1077-1086.
²³
Shahani N, Brandt R. Functions and malfunctions of the tau proteins. Cell Mol Life Sci 2002;39:1668-1680.
²⁴
Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 1992; 3: 1141-1154.
²⁵
Hernández F, Avila J. Tauopathies. Cell Mol Life Sci 2007;64: 2219-2233.
²⁶
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Rev Brain Res 2000; 33:95-130.
²⁷
Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 2007;25:59-68.
²⁸
Vuillet J, Dimova R, Nieoullon A, Kerkerian-Le Goff L. Ultrastructural relationships between choline acetyltransferase- and neuropeptide y-containing neurons in the rat striatum. Neuroscience 1992;46:351-360.
²⁹
Anderton BH, Betts J, Blackstock WP, et al. Sites of phosphorylation in tau and factors affecting their regulation. Biochem Soc Symp. 2001;(67):73-80.
³⁰
Lovestone S, Hartley CL, Pearce J, Anderton BH. The phosphorylation of Tau: a critical stage in neurodevelopmental and neurodegenerative processes. Neuroscience 1997; 78:309-324.
³¹
Ribaut-Barassin C, Dupont JL, Haeberlé AM, et al. Alzheimer's disease proteins in cerebellar and hippocampal synapses during postnatal development and aging of the rat. Neuroscience 2003;120:405-423
³²
Iqbal K, Adel C, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochem Biophys Acta 2005;13: 198-210.
³³
Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 2004;117(Pt 24): 5721-5729.
³⁴
Fasulo L, Ugolini G, Visintin M, et al. Cattaneo A The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis. J Neurochem 2000; 75:624-633
³⁵
Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992;256(5054):184-185.
³⁶
Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 2009;118-36.
³⁷
Schmitt HP. Neuro-modulation, aminergic neuro-disinhibition and neuro-degeneration. Draft of a comprehensive theory for Alzheimer disease. Med Hypotheses 2005;65: 1106-1119.
³⁸
Zhu X, Avila J, Perry G, Smith MA, Treating the lesions not the disease. Am J Pathol 2007;170:1457-1459.
³⁹
Selkoe DJ. Amyloid protein and Alzheimer's disease. Sci Am 1991;265:68-71.
⁴⁰
Lippa CF, Morris JC. Alzheimer neuropathology in nondemented aging: keeping mind over matter. Neurology 2006;66: 1801-1802.
⁴¹
Cummings J. Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials. Alzheimer Dement 2006;2:263-271.
⁴²
Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Ab42 immunization in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372:216-223.
⁴³
Swerdlow RH. Pathogenesis of Alzheimer's disease. Clin Interv Aging. 2007;2:347-359.
⁴⁴
Braak H, Tredici KD. Alzheimer's disease: intraneuronal alterations precede insoluble amyloid-b formation. Neurobiol Aging 2004;25:713-718.
⁴⁵
Mazanetz MP, Fischer PM. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov 2007;6:464-479.
⁴⁶
Mandelkow E, von Bergen M, Biernat J, Mandelkow EM.. Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 2007;17:83-90
⁴⁷
Yilmazer-Hanke DM, Hanke J. Progression of Alzheimer-related neuritic plaque pathology in the entorhinal region, perirhinal cortex and hippocampal formation. Dement Geriatr Cogn Disord 1999;10:70-76.
⁴⁸
Grinberg LT, Rüb U, Ferretti RE, et al. Brazilian Brain Bank Study Group. The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset? Neuropathol Appl Neurobiol 2009;35:406-416.
⁴⁹
Bhat RV, Budd SL. GSK3beta signaling: casting a wide net in Alzheimer's disease. Neurosignals 2002;11:251-261.
⁵⁰
Boonen RA, van Tijn P, Zivkovic D. Wnt signaling in Alzheimer's disease: up or down, that is the question. Ageing Res Rev 2009;8:71-82.
⁵¹
Wang Y, Zhang JX, Du XX, et al. Temporal correlation of the memory deficit with Alzheimer-like lesions induced by activation of glycogen synthase kinase-3. J Neurochem 2008;106:2364-2374.
⁵²
Forlenza OV, Spink JM, Dayanandan R, Anderton BH, Olesen OF, Lovestone S. Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3b inhibition and in neurons. J Neural Transm 2000;107:1201-1212.
⁵³
Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA. 2005;102: 6990-6995.
⁵⁴
Mendes CT, Mury FB, de Sá Moreira E, et al. Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease. Eur Arch Psychiatry Clin Neurosci 2009;259:16-22.
⁵⁵
Hye A, Kerr F, Archer N, et al. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease. Neurosci Lett 2005;373:1-4.
⁵⁶
Hooper PL. Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis. Metab Syndr Relat Disord. 2007;5:220-230.

Publication Dates

Publication in this collection
Jul-Sep 2009

History

Received
29 May 2009
Accepted
11 Aug 2009

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Herrera E Jr, Caramelli P, Silveira AS, Nitrini R. Epidemiologic survey of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord 2002;16:103-108.

[2] ²
Nitrini R, Caramelli P, Herrera E Jr, et al. Incidence of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord 2004;18:241-246.

[3] ³
Hestad K, Kveberg B, Engedal K. Low blood pressure is a better predictor of cognitive deficits than the apolipoprotein e4 allele in the oldest old. Acta Neurol Scand 2005;111:323-328.

[4] ⁴
Ravona SR, Davidson M, Noy S. The role of cardiovascular risk factors in Alzheimer's disease. CNS Spectr 2003;8:824-833.

[5] ⁵
Boeras DI, Granic A, Padmanabhan J, Crespo NC, Rojiani AM, Potter H. Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol Aging 2008;29:319-328.

[6] ⁶
Castellani RJ, Lee HG, Zhu XW, Nunomura A, Perry G, Smith MA. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic, Acta Neuropathol 2006;111: 503-509.

[7] ⁷
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-259.

[8] ⁸
Di Luca M, Colciaghi F, Pastorino L, Borroni B, Padovani A, Cattabeni F. Platelets as a peripheral district where to study pathogenetic mechanisms of alzheimer disease: the case of amyloid precursor protein. Eur J Pharmacol 2000;405:277-283.

[9] ⁹
Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1994;57: 419-425.

[10] ¹⁰
Korczyn AD. The amyloid cascade hypothesis. Alzheimers Dement 2008;4:176-178.

[11] ¹¹
Kontush A. Apolipoprotein Abeta: black sheep in a good family. Brain Pathol 2004;14:433-447.

[12] ¹²
Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L. Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS ONE 2008;23:2718.

[13] ¹³
Rhein V, Eckert A. Effects of Alzheimer's amyloid-beta and tau protein on mitochondrial function: role of glucose metabolism and insulin signaling. Arch Physiol Biochem. 2007; 113:131-141.

[14] ¹⁴
Oide T, Kinoshita T, Arima K. Regression stage senile plaques in the natural course of Alzheimer's disease. Neuropathol Appl Neurobiol 2006;32:539-556.

[15] ¹⁵
Vetrivel KS, Thinakaran G. Amyloidogenic processing of b-amyloid precursor protein in intracellular compartments. Neurology 2006;66(2 Suppl 1):S69-S73.

[16] ¹⁶
Kunjathoor VV, Tseng AA, Medeiros LA, Khan T, Moore KJ. b-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins. J Neuroinflammation 2004;16:23.

[17] ¹⁷
Kosik KS. The molecular and cellular biology for tau. Brain Path 1993;3:39-43.

[18] ¹⁸
Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 1984;259:5301-5305.

[19] ¹⁹
Cleveland DW, Hoffman PN. Neuronal and glial cytoskeletons. Curr Opin Neurobiol 1991;1:346-353.

[20] ²⁰
Lovestone S, Anderton B. Cytoskeletal abnormalities in Alzheimer's disease. Curr Opin Neurol Neurosurg 1992;5:883-888.

[21] ²¹
Trojanowski JQ, Lee VM. Paired helical filament tau in Alzheimer's disease. The kinase connection: neurobiology of Alzheimer's disease. Am J Pathol 1994;144:449-453.

[22] ²²
Lovestone S, Reynolds CH, Latimer D, et al. Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 1994;4:1077-1086.

[23] ²³
Shahani N, Brandt R. Functions and malfunctions of the tau proteins. Cell Mol Life Sci 2002;39:1668-1680.

[24] ²⁴
Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 1992; 3: 1141-1154.

[25] ²⁵
Hernández F, Avila J. Tauopathies. Cell Mol Life Sci 2007;64: 2219-2233.

[26] ²⁶
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Rev Brain Res 2000; 33:95-130.

[27] ²⁷
Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 2007;25:59-68.

[28] ²⁸
Vuillet J, Dimova R, Nieoullon A, Kerkerian-Le Goff L. Ultrastructural relationships between choline acetyltransferase- and neuropeptide y-containing neurons in the rat striatum. Neuroscience 1992;46:351-360.

[29] ²⁹
Anderton BH, Betts J, Blackstock WP, et al. Sites of phosphorylation in tau and factors affecting their regulation. Biochem Soc Symp. 2001;(67):73-80.

[30] ³⁰
Lovestone S, Hartley CL, Pearce J, Anderton BH. The phosphorylation of Tau: a critical stage in neurodevelopmental and neurodegenerative processes. Neuroscience 1997; 78:309-324.

[31] ³¹
Ribaut-Barassin C, Dupont JL, Haeberlé AM, et al. Alzheimer's disease proteins in cerebellar and hippocampal synapses during postnatal development and aging of the rat. Neuroscience 2003;120:405-423

[32] ³²
Iqbal K, Adel C, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochem Biophys Acta 2005;13: 198-210.

[33] ³³
Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 2004;117(Pt 24): 5721-5729.

[34] ³⁴
Fasulo L, Ugolini G, Visintin M, et al. Cattaneo A The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis. J Neurochem 2000; 75:624-633

[35] ³⁵
Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992;256(5054):184-185.

[36] ³⁶
Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 2009;118-36.

[37] ³⁷
Schmitt HP. Neuro-modulation, aminergic neuro-disinhibition and neuro-degeneration. Draft of a comprehensive theory for Alzheimer disease. Med Hypotheses 2005;65: 1106-1119.

[38] ³⁸
Zhu X, Avila J, Perry G, Smith MA, Treating the lesions not the disease. Am J Pathol 2007;170:1457-1459.

[39] ³⁹
Selkoe DJ. Amyloid protein and Alzheimer's disease. Sci Am 1991;265:68-71.

[40] ⁴⁰
Lippa CF, Morris JC. Alzheimer neuropathology in nondemented aging: keeping mind over matter. Neurology 2006;66: 1801-1802.

[41] ⁴¹
Cummings J. Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials. Alzheimer Dement 2006;2:263-271.

[42] ⁴²
Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Ab42 immunization in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372:216-223.

[43] ⁴³
Swerdlow RH. Pathogenesis of Alzheimer's disease. Clin Interv Aging. 2007;2:347-359.

[44] ⁴⁴
Braak H, Tredici KD. Alzheimer's disease: intraneuronal alterations precede insoluble amyloid-b formation. Neurobiol Aging 2004;25:713-718.

[45] ⁴⁵
Mazanetz MP, Fischer PM. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov 2007;6:464-479.

[46] ⁴⁶
Mandelkow E, von Bergen M, Biernat J, Mandelkow EM.. Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 2007;17:83-90

[47] ⁴⁷
Yilmazer-Hanke DM, Hanke J. Progression of Alzheimer-related neuritic plaque pathology in the entorhinal region, perirhinal cortex and hippocampal formation. Dement Geriatr Cogn Disord 1999;10:70-76.

[48] ⁴⁸
Grinberg LT, Rüb U, Ferretti RE, et al. Brazilian Brain Bank Study Group. The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset? Neuropathol Appl Neurobiol 2009;35:406-416.

[49] ⁴⁹
Bhat RV, Budd SL. GSK3beta signaling: casting a wide net in Alzheimer's disease. Neurosignals 2002;11:251-261.

[50] ⁵⁰
Boonen RA, van Tijn P, Zivkovic D. Wnt signaling in Alzheimer's disease: up or down, that is the question. Ageing Res Rev 2009;8:71-82.

[51] ⁵¹
Wang Y, Zhang JX, Du XX, et al. Temporal correlation of the memory deficit with Alzheimer-like lesions induced by activation of glycogen synthase kinase-3. J Neurochem 2008;106:2364-2374.

[52] ⁵²
Forlenza OV, Spink JM, Dayanandan R, Anderton BH, Olesen OF, Lovestone S. Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3b inhibition and in neurons. J Neural Transm 2000;107:1201-1212.

[53] ⁵³
Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA. 2005;102: 6990-6995.

[54] ⁵⁴
Mendes CT, Mury FB, de Sá Moreira E, et al. Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease. Eur Arch Psychiatry Clin Neurosci 2009;259:16-22.

[55] ⁵⁵
Hye A, Kerr F, Archer N, et al. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease. Neurosci Lett 2005;373:1-4.

[56] ⁵⁶
Hooper PL. Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis. Metab Syndr Relat Disord. 2007;5:220-230.

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