Morbus Alzheimer: Polyätiologie und multifaktorielle Schrittmacher

Zusammenfassung

Aus der Analyse zahlreicher wissenschaftlicher Arbeiten zu kausalen Ursachen der Alzheimer-Erkrankung geht hervor, dass das Risiko für die Neurodegeneration durch mehrere ätiologische Faktoren mit verschiedenen Belastungen aus Umwelt, Verhalten und Lebensstil erhöht wird. Dysregulationen des Mikrobioms und der Darm-Gehirn-Achse sowie der Stoffwechselachse um Leber und Gehirn stellen dabei wichtige Schrittmacher dar. Genauso wie Schwermetalle, Toxine oder ein Mangel an Omega-3-Fettsäuren, B-Vitaminen und Vitamin D. Faktoren wie Schädel-Hirn-Traumata, Verletzungen der Halswirbelsäule, Postinfektionssyndrome und mitochondriale Dysfunktionen münden in Energiemangel, Insulinresistenz, oxidativen Stress, Entzündungen und entgleiste Signalkaskaden für Advanced Glycation Endproduct (AGE) und der zugehörigen Rezeptoren (RAGE).

Abstract

The analysis of several scientific studies on the underlying causes of Alzheimer’s disease shows, that the risk for a neurodegeneration is increased by several etiological factors with various influences from environment, behavior, and lifestyle. Dysregulations of the microbiome and the brain-intestine axis as well as the metabolic axis around liver and brain are important pacemakers. Just like heavy metals, toxins or a lack of omega-3 fatty acids, B vitamins, and vitamin D. Factors like traumatic brain injuries, cervical spine injuries, post-infectious syndromes, and mitochondrial dysfunctions result in lack of energy, insulin resistance, oxidative stress, inflammations, and derailed signaling cascades for Advanced Glycation Endproduct (AGE) and associated receptors (RAGE).

Schlüsselwörter

Alzheimer-Demenz - Energiestoffwechselstörung - Insulinresistenz - Astrozyten-Entgleisung - Hyperammonämie

Keywords

Alzheimer’s dementia - energy metabolism disorder - insulin resistance - astrocyte derailment - hyperammonemia

• Literatur

• 1 Addis P, Shecterle LM, St Cyr JA. Cellular protection during oxidative stress: a potential role for D-ribose and antioxidants. J Diet Suppl 2012; 9 (03) 178-182
• 2 Agrawal R, Tyagi E, Shukla R. Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol 2011; 21: 261-273
• 3 Aguer C, Gambarotta D, Mailloux RJ. et al. Galactose enhances oxidative metabolism and reveals mitochondrial dysfunction in human primary muscle cells. PLoS One 2011; 6 (12) e28536 DOI: 10.1371/journal.pone.0028536
• 4 Apelt J, Mehlhorn G, Schliebs R. Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. J Neurosci Res 1999; 57: 693-705
• 5 Arluison M, Quignon M, Nguyen P. et al. Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brainean immunohistochemical study. J Chem Neuroanat 2004; a 28: 117-136
• 6 Arluison M, Quignon M, Thorens B. et al. Immunocytochemical localization of the glucose transporter 2 (GLUT2) in the adult rat brain II. Electron microscopic study. JChem Neuroanat 2004; b 28: 137-146
• 7 Baker LD, Cross DJ, Minoshima S. et al. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011; 68: 51-57
• 8 Behl C, Lezoualc’h F, Trapp T. et al. Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology 1997; 138: 1-6
• 9 Bischoff G, Hiestermann K. Die antiketogene Wirkung der Lactose und Galaktose beim Säugling. Monatsschr Kinderheilk 1930; 46: 426
• 10 Bosco D, Fava A, Plastino M. et al. Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis. J Cell Mol Med 2011; 15: 1807-1821
• 11 Butterworth RF. Pathophysiologyof hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 2002; 17 (04) 221-227
• 12 Butterworth RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis 1998; 21 (Suppl. 01) 6-20
• 13 Butterworth RF. Metal toxicity, liver disease and neurodegeneration. Neurotox Res 2010; 18 (01) 100-5 DOI: 10.1007/s12640-010-9185-z
• 14 Correia SC, Santos RX, Perry G. Insulin-resistant brain state: the culprit in sporadic Alzheimer’s disease?. Ageing Res Rev 2011; 10: 264-273
• 15 Craft S. Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 2005; 26 (Suppl. 01) 65-69
• 16 Cura AJ, Carruthers A. The role of monosaccharide transport proteins in carbohydrate assimilation, distribution, metabolism and homeostasis. Compr Physiol 2012; 2: 863-914
• 17 de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2: 1101-1113
• 18 de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimer’s Dis 2005; 7: 45-61
• 19 de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 2012; 9: 35-66
• 20 Duelli R, Kuschinsky W. Brain glucose transporters: relationship to local energy demand. News Physiol Sci 2001; 16: 71-76
• 21 Duelli R, Schröck H, Kuschinsky W. et al. Intracerebroventricular injection of STZ induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci 1994; 12: 737-43
• 22 Eberwein J. Transcription Factors in the Central Nervous System. In: Siegel GJ, Albers RW, Scott TB. et al., Hrsg. Basic Neurochemistry. Molecular, cellular and medical aspects. 7th ed.. Amsterdam: Elsevier; 2006: 459-470
• 23 Elsbernd H, Weyhenmeyer S, Reutter W. et al. Intravenous use of galactose in the therapy of acute hepatic encephalopathy. Gastroenterology 1997; 112 (Suppl. 04) A1260
• 24 Ercan N, Nuttall FQ, Gannon MC. et al. Effects of glucose, galactose and lactose on the plasma glucose and insulin response in persons with non-insulin-dependent diabetes mellitus. Metabolism 1993; 42: 1560-67
• 25 Fang F, Wang QL, Liu GT. FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging. Naunyn Schmiedebergs Arch Pharmacol 2012; 385: 579-585
• 26 Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol 2002; 67 (04) 259-79
• 27 Felipo V, Butterworth RF. Mitochondrial dysfunction in acute hyperammonemia. Neurochem Int 2002; 40 (06) 487-91
• 28 Fried R, Beckmann N, Keller U. et al. Early glycogenolysis and late glycogenesis in human liver after intravenous administration of galactose. Am J Physiol 1996; 270: G14-19
• 29 Friedrich MJ. Insulin Effects Weigh Heavy on the Brain. JAMA 2006; 296 (14) 1717-1718
• 30 Frustaci A, Chimenti C, Ricci R. et al. (Improve- ment in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 2001; 345: 25-32
• 31 Gai W, Schott-Ohly P, Schulte im Walde S. et al. Differential target molecules for toxicity induced by streptozotocin and alloxan in pancreatic islets of mice in vitro. Exp Clin Endocrinol Diabetes 2004; 112: 29-37
• 32 Ganda OP, Soeldner JS, Gleason RE. et al. Metabolic effects of glucose, mannose, galactose, and fructose in man. J Clin Endocrinol Metab 1979; 49: 616-622
• 33 Gannon MC, Khan MA, Nuttall FQ. Glucose appearance rate after the ingestion of galactose. Metabolism 2001; 50: 93-98
• 34 Gerozissis K. Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 2008; 585: 38-49
• 35 Gong C-X, Liu F, Grundke-Iqbal I. et al. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimer’s Dis 2006; 9: 1-12
• 36 Gould GW, Thomas HM, Jess TJ. et al. Expression of human glucose transporters in Xenopus oocytes: kinetic characterization and substrate specificities of the erythrocyte, liver, and brain isoforms. Biochemistry 1991; 30: 5139-5145
• 37 Grillo CA, Piroli GG, Hendry RM. et al. Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res 2009; 1296: 35-45
• 38 Grünblatt E, Salkovic-Petrisic M, Osmanovic J. et al. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 2007; 101: 757-770
• 39 Harik SI. Changes in the glucose transporter of brain capillaries. Can J Physiol Pharmacol 1992; 70: S113-S117
• 40 Heine H. Alzheimer Demenz: Bedeutung der perineuronalen extrazellulären Matrix (PECM). Schweiz Zschr GanzheitsMedizin 2007; 19 (02) 109-117
• 41 Hellweg R, Nitsch R, Hock C. et al. Nerve growth factor and choline acetyltransferase activity levels in the rat brain following experimental impairment of cerebral glucose and energy metabolism. J Neurosci Res 1992; 31: 35-41
• 42 Herrmann C, Göke R, Richter G. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995; 56: 117-126
• 43 Hooijmans CR, Graven C, Dederen PJ. et al. Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res 2007; 1181: 93-103
• 44 Hoyer S, Lannert H. Long-term effects of corticosterone on behavior, oxidative and energy metabolism of parietotemporal cerebral cortex and hip- pocampus of rats: comparison to intracerebroventricular streptozotocin. J. Neural Transm 2008; 115: 1241-1249
• 45 Hoyer S, Oesterreich K, Wagner O. Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type?. J Neurol 1988; 235: 143-148
• 46 Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 2004; 490: 115-125
• 47 Hoyer S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm 2002; 109: 991-1002
• 48 Hoyer S. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm 2002; 109: 341-360
• 49 Kalaria RN, Harik SI. Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem 1989; 53: 1083-1108
• 50 Kosik J, Gil J, Szmigielski S. et al. Prevention of hepatic metastases by liver lectin blocking with D-galactose in stomach cancer patients. A randomized clinical trial. Anticancer Res 1997; 17: 1411-1415
• 51 Kosterlitz H, Wedler HW. Untersuchungen über die Verwertung der Galaktose in physiologischen und pathologischen Zuständen. II. Mitteilung. Die Verwertung der Galaktose beim Diabetes mellitus. Die Galaktose als Ersatzkohlenhydrat.. Z Ges Exp Med. 1933; 87: 397-404
• 52 Kouznetsova E, Klingner M, Sorger D. et al. Developmental and amyloid plaque-related changes in cerebral cortical capillaries in transgenic Tg2576 mice Alzheimer mice. Int J Dev Neurosci 2006; 24: 187-193
• 53 Kumar A, Prakash A, Dogra S. Centella asiatica attenuates D-galactose- induced cognitive impairment, oxidative and mitochondrial dysfunction in mice. Int J Alzheimers Dis 2011; 347569 DOI: 10.4061/2011/347569
• 54 Landgraf R, Mitro A, Hess J. Regional net uptake of 14C-glucose by rat brain under the influence of corticosterone. Endocrinol Exp 1978; 12: 119-129
• 55 Lawreence M, Sapolsky R. Glucocorticoids accelerate ATP loss following metabolic insults in cultured hippocampal neurons. Brain Res 1994; 646: 303-308
• 56 Lee YJ, Kim JE, Hwang IS. et al. Alzheimer’s phenotypes induced by overexpression of human presenilin 2 mutant proteins stimulate significant changes in key factors of glucose metabolism. Mol Med Rep 2013; 7: 1571-1578
• 57 Lester-Coll N, Rivera EJ, Soscia J. et al. Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease. J Alzheimer’s Dis 2006; 9: 13-33
• 58 Li L, Zhang ZF, Holscher C. et al. (Val⁸) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains. Eur J Pharmacol 2012; 674: 280-286
• 59 Liu F, Iqbal K, Grundke-Iqbal I. et al. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U S A 2004; 101: 10804-10809
• 60 Liu Y, Liu F, Iqbal K. et al. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 2008; 582 (02) 359-364
• 61 Mayer G, Nitsch R, Hoyer S. Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 1990; 532: 95-100
• 62 McClean PL, Parthsarathy V, Faivre E. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 2011; 31: 6587-6594
• 63 McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 2004; 490: 13-24
• 64 Mehla J, Pahuja M, Gupta YK. Streptozotocin-induced sporadic Alzheimer’s disease: selection of appropriate dose. J Alzheimers Dis 2013; 33: 17-21
• 65 Mohammad MA, Sunehag AL, Rodriguez LA. et al. Galactose promotes fat mobilization in obese lactating and nonlactating women. Am J Clin Nutr 201 93 (02) 374-381
• 66 Morfini GA, Stenoien DL, Brady ST. et al. Axonal Transport. In: Siegel GJ, Albers RW, Scott TB. et al. Basic Neurochemistry. Molecular, cellular and medical aspects. 7th ed.. Amsterdam: Elsevier; 2006: 485-501
• 67 Mueckler M. Facilitate glucose transporters. Eur J Biochem 1994; 219: 713-25
• 68 Nitsch R, Hoyer S. Local action of the diabetogenic drug streptozotocin on glucose and energy metabolism in rat brain cortex. Neurosci Lett 1991; 128: 199-202
• 69 Pathan AR, Viswanad B, Sonkusare SK. et al. Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced memory impairment in rats. Life Sci 2006; 79: 2209-2216
• 70 Patil S, Melrose J, Chan C. Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons. Eur J Neurosci 2007; 26: 2131-2141
• 71 Phillips LK, Prins JB. Update on incretin hormones. Ann N Y Acad Sci 2011; 1243: E55-E74
• 72 Pirchl M, Humpel C. Galactose Counteracts Hypoglycemia-Induced Decline of Cholinergic Neurons at Low pH in Organotypic Rat Brain Slices of the Basal Nucleus of Meynert. Pharmacology 2011; 88: 245-251
• 73 Prickaerts J, Blokland A, Honig W. et al. Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-L-carnitine. Brain Res 1995; 674: 142-146
• 74 Prickaerts J, Fahrig T, Blokland A. Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis. Behav Brain Res 1999; 102: 73-88
• 75 Roser M, Josic D, Kontou M. et al. Metabolism of galactose in the brain and liver of rats and its conversion into glutamate and other amino acids. J Neural Transm 2009; 116: 131-39
• 76 Salkovic-Petrisic M, Hoyer S. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J NeuralTransm Suppl 2007; 72: 217-233
• 77 Salkovic-Petrisic M, Osmanovic J, Grünblatt E. et al. Modeling sporadic Alzheimer’s disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities inclusive hyper- phosphorylated tau protein and amyloid-b. A synthesis. J Alzheimer’s Dis 2009; 18: 729-750
• 78 Salkovic-Petrisic M, Osmanovic-Barilar J, Brückner MK. et al. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study. J Neural Transm 2011; 118: 765-772
• 79 Salkovic-Petrisic M, Tribl F, Schmidt M. et al. Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem 2006; 96: 1005-1015
• 80 Salkovic-Petrisic M, Osmanovic-Barilar J, Knezovic A. at al. Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin. Neuropharmacology 2013; 77: 68-80
• 81 Salkovic-Petrisic M, Knezovic A, Hoyer S. et al. What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. J Neural Transm 2013; 120: 233-252
• 82 Savin VJ, McCarthy ET, Sharma R. Galactose binds to focal segmental glomerulosclerosis permeability factor and inhibits its activity. Translational Res 2008; 151: 288-292
• 83 Schulz H, Heck H. Laktat und Ammoniakverhalten bei erschöpfenden Dauerbelastungen. In: Bartmus U, Jendrusch G, Heneke T. et al., Hrsg. In memoriam Horst de Marées anlässlich seines 70. Geburtstages. Beiträge aus Sportmedizin, Trainings- und Bewegungswissenschaft. Köln: Sportverlag Strauß; 2006: 97-107
• 84 Seatter MJ, Kane S, Porter LM. et al. Structure-function studies of the brain-type glucose transporter, GLUT3: alanine-scanning mutagenesis of putative transmembrane helix VIII and an investigation of the role of proline residues in transport catalysis. Biochemistry 1997; 36: 6401-6407
• 85 Seiler N. Ammonia and Alzheimer’s disease. Neurochem Int 2002; 41: 189-207
• 86 Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci 2001; 68: 1021-1029
• 87 Shoham S, Bejar C, Kovalev E. et al. Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol 2003; 84: 1043-1052
• 88 Shoham S, Bejar C, Kovalev E. et al. Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats. Neuropharmacology 2006; 52: 836-843
• 89 Simpson IA, Davies P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimers disease. Ann Neurol 1994; 35: 546-551
• 90 Sparks JW, Avery GB, Fletcher AB. Parenteral galactose therapy in the glucose-intolerant premature infant. J Pediatr 1982; 100: 255-259
• 91 Um HS, Kang EB, Leem YH. et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/APPsw-transgenic model. Int J Mol Med 2008; 22: 529-539
• 92 Vannucci SJ, Koehler-Stec EM, Li K. et al. GLUT4 glucose transporter expression in rodent brain: effect of diabetes. Brain Res 1998; 797: 1-11
• 93 Virgin Jr CE, Ha TPT, Packan DR. et al. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticosteroid neurotoxicity. J Neurochem 1991; 57: 1422-1428
• 94 Warburg O, Posener K, Negelein E. Über den Stoffwechsel der Carcinomzelle. Biochem Z 1924; 152: 309-344
• 95 Wei H, Li L, Song Q. et al. Behavioural study of the D-galactose induced aging model in C57BL/6J mice. Behav Brain Res 2005; 157: 245-251
• 96 Weinstock M, Shoham S. Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm 2004; 111: 347-366
• 97 Wilder and Kitchen. J Amer Med Ass 1923; 80 1642 (cited according to Kosterlitz and Wedler; 1933)