Pathomechanismen und hypothesengeleitete Therapieoptionen bei der Spätform der Alzheimer-Krankheit

S. Hoyer; P. Riederer

doi:10.1055/s-2003-40501

Fortschritte der Neurologie · Psychiatrie, Table of Contents

Fortschr Neurol Psychiatr 2003; 71: 16-26
DOI: 10.1055/s-2003-40501

Originalarbeit

Pathomechanismen und hypothesengeleitete Therapieoptionen bei der Spätform der Alzheimer-Krankheit

Pathomechanisms and Hypothesis-Guided Therapeutic Strategies for Late-Onset Alzheimer's DiseaseS. Hoyer¹ , P. Riederer²

¹Abteilung für Pathochemie und Allgemeine Neurochemie, Universität Heidelberg
²Klinische Neurochemie, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universität Würzburg und NPF Center of Excellence Research Laboratories

Abstract

Zusammenfassung

Obwohl die klinische Wirksamkeit der in der gegenwärtigen Therapie der sporadischen AK eingesetzten Pharmaka ausreichend belegt erscheint, sind ihre Wirkungsmechanismen weit weniger gut bekannt oder werden bei der Beurteilung der klinischen Effekte außer Acht gelassen. Es erscheint jedoch unumgänglich, klinische Wirkung und Wirkungsmechanismen von Pharmaka zu kennen, um ihren Schaden und Nutzen zu beurteilen. Hinsichtlich der bei der sporadischen AK in der Bundesrepublik Deutschland zur Anwendung kommenden Pharmaka zeigen sich völlig unterschiedliche Wirkungsmechanismen. Unter Berücksichtigung der dargestellten Pathomechanismen, die bei sporadischer AK in unterschiedlicher Weise bekannt geworden sind, ergibt sich eine therapeutische Rationale für einen Einsatz von Ginkgo-biloba-Extrakt (EGb 761) und Memantin. Die Anwendung von Azetylcholinesterasehemmern, die vielfach als Mittel der Wahl angesehen werden, ist wegen der Gefahr des Auftretens myopathischer Störungen bzw. des Gulf-War-Syndroms als kritisch zu betrachten. Als viel versprechend apostrophierte und vorschnell propagierte Therapiestrategien mit Statinen oder Vaccination gegen βA4 sollten wegen fehlender Angriffspunkte im bekannten pathophysiologischen Schädigungsmuster der sporadischen AK nicht angewendet werden. Zukünftige Entwicklungen müssten berücksichtigen, dass bei der sporadischen AK nicht oder nur schwer zu therapierende Alterseinflüsse vorliegen. Therapieziele sollten in der Verbesserung des zellulären Energiestatus und der Membranfunktion bestehen.

Abstract

Even though the clinical effectiveness of the presently used pharmaceutical therapy of sporadic Alzheimer Disease seems to be proven sufficient, their effective mechanisms are much less known or are disregarded in the evaluation of the clinical effects. However, it seems to be inevitable to know both clinical effect and effective mechanisms of pharmaceutics in order to be able to judge their adversity and benefit. In reference to the pharmaceutics implemented on sporadic AD in Germany, total different effective mechanisms are shown. In consideration of the shown pathomechanisms which have been recognized for sporadic AD, therapeutic rationales on application of Ginkgo biloba extract (EGb 761) and Memantine are evident. The application of acetylcholinesterase inhibitors, often looked on as agent of choice, is to be considered critically because of the danger of the occurrence of myopathical dysfunction, resp. the Gulf War Syndrome. Sophisticated and hastily advertised therapy strategies with statines or vaccination against βA4 should not be used because of a lack of sufficient evidence based on the pathophysiological pattern of damage as known in sporadic AD. Future development must take in account that with sporadic AD aging influences cannot or can hardly be influenced. Therapeutic goals should consist to improve the cellular energy status and the membrane functioning.

Full Text

References

Literatur

1 Pericak-Vance M, Haines J L. Genetic susceptibility to Alzheimer disease. Trends Genet. 1995; 11 504-508
2 Tilley L, Morgan K, Kalsheker N. Genetic risk factors in Alzheimer's disease. J Clin Pathol Mol Pathol. 1998; 51 293-304
3 Pericak-Vance M A, Grubber J, Baily L R, Hedges D, West S, Santoro L, Kemmerer B, Hall J L, Saunders A M, Roses A D. et al . Identification of novel genes in late-onset Alzheimer's disease. Exp Geront. 2000; 35 1343-1352
4 Holness M J, Langdown M L, Sugden M C. Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of type 2 diabetes mellitus. Biochem J. 2000; 349 657-665
5 Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997; 20 154-159
6 Selkoe D J. Alzheimer's disease: genotypes, phenotype, and treatment. Science. 1997; 275 630-631
7 Joseph J, Shukitt-Hale B, Denisova N A, Martin A, Perry G, Smith M A. Copernicus revisited: amyloid beta in Alzheimer's disease. Neurobiol Aging. 2001; 22 131-146
8 Bancher C, Jellinger K, Lassmann H, Fischer P, Leblhuber F. Correlations between mental state and quantitative neuropathology in the Vienna Prospective Longitudinal Study on Dementia. Eur Arch Psychiatry Clin Neurosci. 1996; 246 137-146
9 Bennett D A, Cochran E J, Saper C B, Leverenz J B, Gilley D W, Wilson R S. Pathological changes in frontal cortex from biopsy to autopsy in Alzheimer's disease. Neurobiol Aging. 1993; 14 589-596
10 Perry E K, Perry R H, Tomlinson B E, Blessed G, Gibson P H. Coenyzm A-acetylating enzymes in Alzheimer's disease: possible cholinergic “compartment” of pyruvate dehydrogenase. Neurosci Lett. 1980; 18 105-110
11 Drachman D A, Noffsinger D, Sahakian B J, Kurdziel S, Fleming P. Aging, memory and the cholinergic system: a study of dichotic listening. Neurobiol Aging. 1980; 1 39-43
12 Michikawa M, Yanagisawa K. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J Neurochem. 1999; 72 2278-2285
13 Pettegrew J W, Klunk W E, Panchalingam K, McCLure R J, Stanley J A. Molecular insights into neurodevelopmental and neurodegenerative diseases. Brain Res Bull. 2000; 53 455-469
14 Rupprecht R, Holsboer F. Neuroactive steroids: mechanism of action and neuropharmacological perspectives. Trends Neurosci. 1999; 22 410-416
14a Dietschy J M, Rürley S D. Cholesterol metabolism in the brain. Curr Op Lipidol. 2001; 12 106-112
14b Schönknecht P, Lütjohann D, Pantel J, Bardenheuer H, Hartmann T, Bergmann K von, Beyreuther K, Schröder J. Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer's disease compared to healthy controls. Neurosci Lett. 2002; 324 83-85
15 Chang W J, Rothberg G K, Kamen B A, Anderson R G. Lowering the cholesterol content of MA 104 cells inhibits receptor-mediated transport by folate. J Cell Biol. 1992; 118 63-69
16 Schnitzer J E, Oh P, Pinney E, Allard J. Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis and capillary permeability of select macromolecules. J Cell Biol. 1994; 127 1217-1232
17 Smith R M, Harada S, Smith J A, Zhang S, Jarett L. Insulin-induced protein tyrosine phosphorylation cascade and signalling molecules are localized in a caveolin-enriched cell membrane domain. Cell Signal. 1998; 10 355-362
18 Gustavsson J, Parpal S, Karlsson M, Ramsing C, Thorn H, Borg M, Lindroth M, Peterson K H, Magnusson K E, Stralfors P. Localization of the insulin receptor in caveolae of adipocyte plasma membrane. FASEB J. 1999; 13 1961-1971
19 Mauch D H, Nägler K, Schumacher S, Göritz E C, Otto A, Pfrieger F W. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001; 294 1354-1357
20 Hoyer S, Frölich L, Sandbrink R. Molekulare Medizin der Alzheimer Krankheit. In: Ganten D, Ruckpaul K (Hrsg.). Handbuch der molekularen Medizin, Bd. 5: Erkrankungen des Zentralnervensystems. Berlin-Heidelberg: Springer 1999: 195-236
21 Müller W E, Mutschler E, Riederer P. Noncompetitive NMDA Receptor Antagonists with Fast Open-Channel Blocking Kinetics and Strong Voltage-Dependency as Potential Therapeutic Agents for Alzheimer's Dementia. Pharmacopsychiat. 1995; 28 113-124
22 Henneberg N, Hoyer S. Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)?. Arch Gerontol Geriatr. 1995; 21 63-74
23 Hoyer S. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: An update. J Neural Transm. 2002; 109 341-360
23a Bernstein H G, Ansorge S, Riederer P, Reiser M, Frölich L, Bogerts B. Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques. Neurosci Letters. 1999; 263 161-164
24 Abbott M A, Wells D G, Fallon J R. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J Neurosci. 1999; 19 7300-7308
25 Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon M J, Alkon D L. Brain insulin receptors and spatial memory. J Biol Chem. 1999; 274 34 893-34 902
26 Solano D J, Sironi M, Bonfini C, Solerte B, Govoni S, Racchi M. Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J. 2000; 14 1015-1022
27 Gasparini L, Gouras G K, Wang R, Gross R S, Beal M F, Greengard P, Xu H. Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneural β-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001; 21 2561-2570
28 Hoyer S. Senile dementia and Alzheimer's disease: brain blood flow and metabolism. Prog Neuropsychopharmacol Biol Psychiatry. 1986; 10 447-478
29 Salehi M, Hodgkins B J, Merry B J, Goyns M H. Age-related changes in gene expression in the rat brain revealed by differential display. Experientia. 1996; 52 888-891
30 Wu H C, Lee E HY. Identification of a rat brain gene associated with aging by PCR differential display method. J Mol Neurosci. 1997; 8 13-18
31 Jiang C H, Tsien J Z, Schultz P G, Hu Y. The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc Natl Acad Sci USA. 2001; 98 1930-1934
32 Hoyer S. The effect of age on glucose and energy metabolism in brain cortex of rats. Arch Gerontol Geriatr. 1985; 4 193-203
33 Bowen D M. Cellular aging: selective vulnerability of cholinergic neurons in human brain. Monogr Dev Biol. 1984; 17 42-59
34 Harik S I, McCracken K A. Age-related increase in presynaptic noradrenergic markers of the rat cerebral cortex. Brain Res. 1986; 381 125-130
35 Perego C, Vetrugno C C, De Simono M G, Algeri S. Aging prolongs the stress-induced release of noradrenaline in rat hypothalamus. Neurosci Lett. 1993; 157 127-130
36 Frölich L, Blum-Degen D, Bernstein H G, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Türk A, Hoyer S. et al . Insulin and insulin receptors in the brain in aging and sporadic Alzheimer's disease. J Neural Transm. 1998; 105 423-438
37 Swaab D F, Raadsheer F C, Endert E F, Hofman M A, Kamphorst W C, Ravid R. Increases in cortisol levels in aging and Alzheimer's disease in postmortem cerebrospinal fluid. J Neuroendocrinol. 1994; 6 681-687
38 Söderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease. Lipids. 1991; 26 412-425
39 Igbavboa U, Avdulov A, Schröder F, Wood W G. Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membranes of mice. J Neurochem. 1996; 66 1717-1725
40 Wurtman R J. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci. 1992; 15 117-122
41 Subbarao K V, Richardson J S, Hug L C. Autopsy samples of Alzheimer's cortex show increased lipid perpidation in vitro. J Neurochem. 1990; 55 342-345
42 Mesulam M M. Neuroplasticity failure in Alzheimer's disease. bridging the gap between plaques and tangles. Neuron. 1999; 24 521-529
43 Bak P, Tang C, Wiesenfeld K. Self-organized criticality. Phys Rev A. 1988; 38 364-374
44 Held G A, Solina D H, Keane D T, Haag W J, Horn P M, Grinstein G. Experimental study of critical-mass fluctuations in an evolving sandpile. Physic Rev Lett. 1990; 69 1120-1123
45 Hoyer S, Nitsch R, Oesterreich K. Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: a cross sectional comparison against advanced late-onset and incipient early-onset cases. J Neural Transm (P-D Sect). 1991; 3 1-14
46 Fukuyama H, Ogawa M, Yamauchi H, Yamaguchi S, Kimua J, Yonekura Y, Konichi J. Altered cerebral energy metabolism in Alzheimer's disease: a PET study. J Nucl Med. 1994; 35 1-6
47 Peskind E R, Elrod R, Dobie D J, Pascualy M, Petrie E, Jensen C, Brodkin M, Murray S, Veith R C, Raskind M A. Cerebrospinal fluid nonepinephrine in Alzheimer's disease and normal aging. Neuropsychopharmacology. 1998; 19 465-471
48 Hoyer S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Exp Gerontol. 2000; 35 1363-1372
49 Hoyer S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm. 1988; 105 415-422
50 Hong M, Lee V MY. Insulin and insulin-like growth factor-1 regulate τ phosphorylation in cultured human neurons. J Biol Chem. 1997; 272 19 547-19 553
51 Mandelkow E M, Drewes G, Biernat J, Gustke N, Lint J van, Vandenheede J R, Mandelkow E. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein τ. FEBS Lett. 1992; 314 315-321
52 Münch G, Schinzel R, Loske C, Wong A, Durany N, Li J J, Vlassara H, Smith M A, Perry G, Riederer P. Alzheimer's disease-synergistic effects of glucose deficit, oxidative stress and advanced glycation end products. J Neural Transm. 1998; 105 439-461
53 Sims N R, Bowen D M, Neary D, Davison A N. Metabolic processes in Alzheimer's disease: adenine nucleotide content and production of ¹⁴C0₂ from (U¹⁴C) glucose in vitro in human neocortex. J Neurochem. 1983; 41 1329-1334
54 Hoyer S. Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases. Mol Chem Neuropathol. 1992; 16 207-224
55 Gibson G E, Jope R, Blass J P. Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces. Biochem J. 1975; 148 17-23
56 Sims N R, Bowen D M, Davison A N. (¹⁴C) acetylcholine synthesis and (¹⁴C) carbon dioxide productin from (U ¹⁴C) glucose by tissue prisms from human neocortex. Biochem J. 1981; 196 867-876
57 Münch G, Lüth H J, Wong A, Arendt Th, Hirsch E, Ravid R, Riederer P. Crosslinking of α-synuclein by advanced glycation endproducts - an early pathophysiological step in Lewy body formation?. J Chem Neuroanat. 2000; 20 253-257
58 Buttgereit F, Brand M D. A hierarchy of ATP-consuming processes in mammalian cells. Biochem J. 1995; 312 163-167
59 Röder H M, Ingram V M. Two novel kinases phosphorylate τ and the KSP site of heavy neurofilament subunits in high stoichiometric ratios. J Neurosci. 1991; 11 3325-3343
60 Bush M L, Niyashiro J S, Ingram V M. Activation of a neurofilament kinase, a τ kinase and a τ phosphatase by decreased ATP levels in nerve growth factor-differentiated PC 12 cells. Proc Natl Acad Sci USA. 1995; 92 1962-1965
61 Wilson C A, Doms R W, Lee V MY. Intracellular APP processing and Aβ production in Alzheimer disease. J Neuropathol Exp Neurol. 1999; 58 787-794
62 Gouras G K, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield J P, Haroutunian V, Buxbaum J D, Xu H, Greengard P, Relkin N R. Intraneural Aβ42 accumulation in human brain. Am J Pathol. 2000; 156 15-20
63 Nitsch R M, Rebeck G W, Deng M, Richardson U I, Tennis M, Schenk D B, Vigo-Pelfrey C, Lieberburg I, Wurtman R J, Hyman B T, Growdon J H. Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease: inverse correlation with severity of dementia and effect of apolipoprotein E genotype. Ann Neurol. 1995; 37 512-518
64 Schröder J, Pantel J, Ida N, Essig M, Hartmann T, Knopp M V, Schad L R, Sandbrink R, Sauer H, Masters C L, Beyreuther K. Cerebral changes and cerebrospinal fluid β-amyloid in Alzheimer's disease: a study with quantitative magnetic resonance imaging. Mol Psychiatry. 1997; 2 505-507
65 Kanai M, Matsubara E, Isoe K, Urakami K, Nakashima K, Arai H, Sasaki H, Abe K, Iwatsubo T, Kosaka T. et al . Longitudinal study of cerebrospinal fluid levels of τ, Aβ1 - 40, and Aβ1 - 42 (43) in Alzheimer's disease: A study in Japan. Ann Neurol. 1998; 44 17-26
66 Tapiola T, Pirttilä T, Mikkonen M, Mehta P D, Alafuzoff I, Koivisto K, Soininen H. Three-year follow-up of cerebrospinal fluid τ, β-amyloid 42- and 40 concentrations in Alzheimer's disease. Neurosci Lett. 2000; 280 119-122
66a Nostrand W E van, Wagner S L, Rodman Shankle W, Farrour J S, Dick M, Rozemüller J M, Kuiper M A, Wolters E C, Zimmermann J, Cotman C W, Cunningham D D. Decreased levels of soluble amyloid β-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci USA. 1992; 89 2551-2555
66b Sennvik K, Fastbom J, Blomberg M, Wahlund L O, Winblad B, Benedikz E. Levels of α- and β-secretase cleared amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients. Neurosci Lett. 2000; 278 169-172
67 Davidsson P, Bogdanovic N, Lannfeldt L, Blennow K. Reduced expression of amyloid precursor protein, presenilin-1 and rab 3a in cortical brain regions in Alzeimer's disease. Dement Geriatr Cogn Dis. 2001; 12 243-250
68 Hoyer S, Nitsch R. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J Neural Transm. 1989; 75 227-232
69 Hoyer S, Nitsch R, Oesterreich K. Ammonia is endogenously generated in the brain in the presence of presumed and verified dementia of Alzheimer type. Neurosci Lett. 1990; 117 358-362
70 Blandini F, Sand P, Riederer P, Greenamyre J T. Parkinson's Disease-Neuroprotection. In: Lodge D, Danysz W, Parsons G (eds.). Ionotropic glutamate Receptors as Therapeutic Targets. Johnson City, TN: Graham Publishing Co. 2002 in press
71 Scorrano L, Petronilli V, Bernard P. On the voltage dependence of the mitochondrial permeability transition pore - a critical appraisal. J Biol Chem. 1997; 272 12 295-12 299
72 Gsell W, Strein I, Riederer P. The neurochemistry of Alzheimer type, vascular type and mixed type dementias compared. J Neural Transm. 1996; (Suppl) 47 73-101
73 Schnurra I, Bernstein H G, Riederer P, Braunewell K H. The Neuronal Calcium Sensor Protein VILIP-1 Is Associated with Amyloid Plaques and Extracellular Tangles in Alzheimer's Disease and Promotes Cell Death and Tau Phosphorylation in Vitro: A Link between Calcium Sensors and Alzheimer's Disease?. Neurobiol Dis. 2001; 8 900-909
74 Retz W, Kornhuber J, Riederer P. Neurotransmission and the ontogeny of human brain. J Neural Transm. 1996; 103 403-419
75 Cruz-Sánchez F F, Durany N, Thome J, Riederer P, Zambón D. Correlation between Apolipoprotein-E Polymorphism and Alzheimer's Disease Pathology. J of Alzheimer's Disease. 2000; 2 223-229
76 Retz W, Thome J, Durany N, Harsányi A, Retz-Junginger P, Kornhuber J, Riederer P, Rösler M. Potential genetic markers of sporadic Alzheimer's dementia. Psychiatric Genetics. 2001; 11 115-122
77 Sun F F, Fleming W E, Taylor B M. Degradation of membrane phospholipids in the cultured human astroglial cell line UC-11MG during ATP depletion. Biochem Pharmacol. 1993; 45 1149-1155
78 Nitsch R M, Blusztayn J K, Pittas A G, Slack B E, Growdon J H, Wurtman R J. Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci USA. 1992; 89 1671-1675
79 Bogdanovic N, Bretillon L, Lund E G, Diczfalusy U, Lannfelt L, Winblad B, Russell D W, Björkhem I. On the turnover of brain cholesterol in patients with Alzheimer's disease. Hormonal induction of the cholesterol - catabolic enzyme CYP 46 in glial cells. Neurosci Lett. 2001; 314 45-48
80 Mason R P, Shoenmaker W J, Shajenko L, Chambers T, Herbette L G. Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol. Neurobiol Aging. 1992; 13 413-419
81 Mulder M, Ravid R, Swaab D F, de Kloet E R, Haasdijk E D, Julk J, Boom J van der, Havekes L M. Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis Ass Disord. 1998; 12 198-203
82 Lütjohann D, Papassotiropoulos A, Björkhem I, Locatelli S, Bagli M, Oehring R D, Schlegel U, Jessen F, Rao M L, Bergmann K von, Heun R. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res. 2000; 41 195-198
83 Papassotiropoulos A, Lütjohann D, Bagli M, Locatelli S, Jessen F, Rao M L, Maier W, Björkhem I, Bergmann K von, Heun R. Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker of Alzheimer's disease. NeuroReport. 2000; 11 1959-1962
84 Wu Y, Sun F F, Tong D M. Changes in membrane properties during energy depletion-induced cell injury studied with fluorescence microscopy. Biophys J. 1996; 71 91-100
85 Klein J. Membrane breakdown in acute and chronic neurodegeneration. Focus on choline-containing phospholipids. J Neural Transm. 2000; 107 1027-1063
85a Kirsch C, Eckert G P, Müller W E. Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol. 2003; 65 843-856
85b Fan Q W, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of τ phosphorylation in cultured neurons. J Neurochem. 2002; 76 391-400
85c Meske V, Albert F, Richter D, Schwarze J, Ohm T G. Blockade of HMG-COA reductase activity causes changes in suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease. Euro J Neurosci. 2003; 17 93-102
85d Müller W E, Kirsch C, Eckert G P. Membrane-disordering effects of β-amyloid peptides. Biochem Soc Trans. 2001; 29 617-623
86 Heiss W D, Hebold T, Klinkhammer P, Ziffling P, Szelies B, Pawlik G, Herholz K. Effect of piracetam on cerebral glucose metabolism in Alzheimer's disease as measured by positron emission tomography. J Cereb Blood Flow Metabol. 1988; 8 613-617
87 Scheuer K, Rostock A, Bartsch R, Müller W E. Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain. Pharmacopsychiatry. 1999; 32 (Suppl) 10-16
88 Müller W E, Koch S, Scheuer K, Rostock A, Bartsch R. Effects of piracetam on membrane fluidity in the aged mouse rat, and human brain. Biochem Pharmacol. 1997; 53 135-140
89 Hoyer S, Lannert H, Nöldner M, Chatterjee S S. Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761). J Neural Transm. 1999; 106 1171-1188
90 Stoll S, Scheuer K, Pohl O, Müller W E. Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse. Pharmacopsychiatry. 1996; 29 144-149
91 Watanabe C MH, Wolffram S, Ader P, Rimbach G, Packer L, Maguire J J, Schultz P G, Gohil K. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc Natl Acad Sci USA. 2001; 98 6577-6580
91a Huri H, Ogwuegbu S O, Boujard N, Drieu D, Papedopulus V. In vivo granulation of the peripheral-type benzodiazepine receptor and glucocorticoid syntheses by the Ginkgo biloba extract 761 and isolated gingkolides. Endocrinology. 1996; 137 5707-57 18
92 Le Bars P L, Katz M M, Berman N, Itil T M, Freedman A M, Schatzberg A F. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. J Amer Med Ass. 1997; 278 1327-1332
93 Sims N R, Bowen D M, Allen S J, Smith T TC, Neary D, Thomas D J, Davison A N. Presynaptic cholinergic dysfunction in patients with dementia. J Neurochem. 1993; 40 503-509
94 Kaufer D, Friedman A, Seidman S, Soreq H. Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature. 1998; 393 373-377
95 Sapolsky R M. The stress of Gulf War syndrome. Nature. 1998; 393 308-309
96 Kammer H von der, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch R M. Muscarinic acetylcholine receptors activate expression of the Egr gene family of transcription factors. J Biol Chem. 1998; 273 14 538-14 544
97 Davidsson P, Blennow K, Andreasen N, Eriksson B, Minthon L, Hesse C. Differential increase in cerebrospinal fluid-acetylcholinesterase after treatment with acetylcholinesterase inhibitors in patients with Alzheimer's disease. Neurosci Lett. 2001; 300 157-160
98 Woodruff-Pak D S, Vogel III R W, Wenk G L. Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci USA. 2001; 98 2089-2094
99 Jeyrasasingam G, Yeluashvili M, Quik M. Tacrine, a reversible acetylcholinesterase inhibitor, induces myopathy. NeuroReport. 2000; 11 1173-1176
100 Lahiri D K, Farlow M R, Hintz N, Utsuki T, Greig N H. Cholinesterase inhibitors, β-amyloid precursor protein and amyloid β-peptides in Alzheimer's disease. Acta Neurol Scand Suppl. 2000; 176 60-67
101 Kornhuber J, Weller M, Schoppmeyer K, Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Tansm. 1994; 43 (Suppl) 91-104
102 Winblad B, Poritis N. Memantine in severe dementia: results of the M-Best study (Benefit and efficacy in severly demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999; 14 135-146
103 Heidrich A, Rösler M, Riederer P. Pharmakotherapie bei Alzheimer-Demenz: Therapie kognitiver Symptome - neue Studienresultate. Fortschr Neurol Psychiat. 1997; 65 108-121
103a Iqbal K. Neurofibrillary Degeneration: A Promising Target for the Treatment of Alzheimer's disease and other Tauopathies. Seville: Abstract book, p 42, Int. Conf. AD/PD 2003
103b Alvarez X A, Lombardi V, Sampedro C, Corzo L, Zas Z, Perez P, Laredo M, Couceiro V, Astoreka I, Varela M, Fernandez-Novoa L, Cacabelos R, Stoeffler A, Moebius H J. Genotype-Related Reduction of Apoptosis in Alzheimer's disease Patients treated with Memantine. Seville: Abstract book, p 54, Int. Conf. AD/PD 2003
103c Reisberg B, Stoeffler A, Ferris S, Schmitt F, Doody R S, Moebius H J. A placebo-controlled study of memantine in advanced Alzheimer's disease. New England J Med. 2003; 348 1333-1341
104 Gerlach M, Youdim M BH, Riederer P. Pharmacology of selegiline. Neurology. 1996; 47 (Suppl 3) 2137-2145
105 Mahley R. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988; 240 622-630
106 Simons M, Keller P, De Strooper B, Beyreuther K, Dotti C, Simons K. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci USA. 1998; 95 6460-6464
107 Endo A, Hasumi K. Biochemical aspects of HMG CoA reductase inhibitors. Ad Enzyme Regul. 1989; 28 53-64
108 Jick H, Zornberg G L, Jick S S, Seshadri S, Drachman D A. Statins and the risk of dementia. Lancet. 2000; 356 1627-1631
109 Wolozin B, Kellman W, Ruosseau P, Celesia G G, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3 methyl-glutaryl Coenzyme A reductase inhibitors. Arch Neurol. 2000; 57 1439-1443
110 Blennow K, Wallin A. Clinical heterogeneity of probable Alzheimer's disease. J Geriatr Psychiatry Neurol. 1992; 5 106-113
111 Fassbender K, Simons M, Bergmann C, Stroick M, Lütjohann D, Keller P, Runz H, Kühl S, Bertsch T, Bergmann K von, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. Proc Natl Acad Sci USA. 2001; 98 5856-5861
112 Eckert G P, Kirsch C, Müller W E. Differential effects of lovostatin treatment on brain cholesterol levels in normal and ApoE-deficient mice. NeuroReport. 2001; 12 883-887
112a Simons M, Schwärzler I, Lütjohann D, Bergmann K von, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz J B. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomised, placebo-controlled, double-blind trial. Ann Neurol. 2002; 52 346-350
112b Sjorgren M JC, Gustafsson K, Syversen S, Olsson A, Wallin A, Blennow K. Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein. Seville: Abstract book, p 47, Int. Conf. AD/PD 2003
112c Yanagisawa K. Cholesterol and Aβ cascade: Pathological implication of Apolipoproteine in Alzheimer's disease. Seville: Abstract book, p 123, Int. Conf. AD/PD 2003
113 Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K. Cholesterol-dependent formation of GM1 ganglioside-bound amyloid β-protein, an endogenous seed for Alzheimer amyloid. J Biol Chem. 2001; 276 24985-24990
114 Birge S J. Mortel KF. Estrogen and the treatment of Alzheimer's disease. Am J Med. 1997; 103 36-45
115 Lannert H, Wirtz P, Schuhmann V, Galmbacher R. Effects of estradiol (β-17) on learning, memory and cerebral energy metabolism in male rats after intracerebroventricular administration of streptozotocin. J Neural Transm. 1998; 105 1045-1063
116 McEwen B S. The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metabol. 1999; 84 1790-1797
117 Blum-Degen D, Haas M, Pohli S, Harth S, Riederer P, Götz M. Scavestrogens protect IMR 32 cells from oxidative stress - induced cell death. Toxicol Pharmacol. 1998; 152 49-55
118 Berchtold N C, Kesslak J P, Pike C J, Adlard P A, Cotman C W. Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus. Eur J Neurosci. 2001; 14 1992-2002
119 Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P E, Sheline Y, Luby J, Dagogo-Jack A, Alderson A. Memory improvement following induced hyperinsulinemia in dementia of the Alzheimer type. Neurobiol Aging. 1996; 17 123-130
120 Manning C A, Ragazzino M C, Gold P E. Glucose enhancement of memory in patients with probable senile dementia of the Alzheimer's type. Neurobiol Aging. 1993; 14 523-528
121 Boyt A A, Taddel K, Hallmayer J, Helmerhorst E, Gandy S E, Craft S, Martins R N. The effect of insulin and glucose on the plasma concentration of Alzheimer's amyloid precursor protein. Neuroscience. 2000; 95 727-734
122 Löffler T, Lee S K, Nöldner M, Chatterjee S S. Effect of Ginkgo biloba extract (EGb 761) on glucose-metabolic-related markers in streptozotocin-damaged rat brain. J Neural Transm. 2001; 108 457-1474
123 Robinson S R, Münch G. Alzheimer's vaccine: a cure worse than the disease?. J Neural Transm. 2002; 109 537-539
124 Check E. Nerve inflammation halts trial for Alzheimer's drug. Nature. 2002; 415 462
125 Braak H, Braak E, Yilmazer D, de Vos R AI, Jansen E NH, Bohl J. Pattern of brain destruction in Parkinson's and Alzheimer's diseases. J Neural Transm. 1996; 103 455-490

Prof. Dr. Peter Riederer

Klinik und Poliklinik für Psychiatrie und Psychotherapie · Klinische Neurochemie

Füchsleinstr. 15

97080 Würzburg

Email: peter.riederer@mail.uni-wuerzburg.de