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Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update
S. Hoyer / Experimental Gerontology 35 (2000) 1363±1372
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Experimental Gerontology 35 (2000) 1363±1372 www.elsevier.nl/locate/expgero
Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update S. Hoyer* Department of Pathochemistry and General Neurochemistry, University of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany Received 3 May 2000; received in revised form 31 May 2000; accepted 31 May 2000
Abstract It is discussed that Alzheimer disease does not form a nosologic entity. 5 to 10% of all Alzheimer cases are due to inherited abnormalities on chromosomes 1, or 14, or 21, whereas the majority of 90± 95% is sporadic in origin. Age-related changes in the composition of membranes and in glucose/ energy metabolism along with a sympathetic tone in the brain are assumed to be cellular/molecular risk factors for this disease. In its pathogenesis, the desensitization of the neuronal insulin receptor similar to non-insulin dependent diabetes mellitus may be of pivotal signi®cance. This abnormality along with a reduction in insulin concentration is assumed to induce a cascade-like process of disturbances including decreases in cellular glucose, acetylcholine, cholesterol, and ATP, associated with changes in the metabolism of amino acids and fatty acids. There is evidence that the reductions in the availability of both glucose/energy and insulin contribute to the formation of amyloidogenic derivatives and hyperphosphorylated tau protein. This may indicate that the amyloid cascade hypothesis in not valid for sporadic Alzheimer disease but that the formation of both, amyloidogenic derivatives and hyperphosphorylated tau protein is downstream the origin of this neurodegenerative disease. q 2000 Elsevier Science Inc. All rights reserved. Keywords: Alzheimer brain; Oxidative metabolism; Insulin signaling
1. Introduction Although Alzheimer disease (AD) looks rather uniform in terms of both the morphological end stage in brain and the clinical feature, there is no evidence that this neurodegenerative disorder originates by one single cause. Evidence is provided that a smaller * Tel.: 149-6221-562618; fax: 149-6221-564228. E-mail address: [email protected] (S. Hoyer). 0531-5565/00/$ - see front matter q 2000 Elsevier Science Inc. All rights reserved. PII: S 0531-556 5(00)00156-X
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Fig. 1. The nosologic heterogeneity of Alzheimer disease.
proportion of 5±10% of all Alzheimer cases is caused by genetic abnormalities on chromosomes 1, or 14, or 21 leading to early-onset AD. These different inherited disturbance serve as the basis of the amyloid cascade hypothesis of AD (Hardy, 1997; Selkoe, 1997). In contrast, the greatest proportion of all Alzheimer cases (95±90%) was found to be of late-onset and sporadic in origin. Allelic abnormalities in the APOE-gene may facultatively contribute to both anticipated onset and severity of early-onset and late-onset AD. For the latter, age-related cellular and molecular changes are considered to be risk factors (for review see Hoyer, 1995) (Fig. 1). Thus, inherited AD and sporadic AD do not form a nosologic entity. There is ®rst evidence that the aging process in the brain is accompanied by variations in gene expression as compared to adult brain in that some genes are switched on whereas other ones are switched off i.e. for cell protection (Salehi et al., 1996; Wu and Lee, 1997). Although as yet not demonstrated, such on-off-mechanisms may be assumed to be of signi®cance in the etiopathogenesis for sporadic AD as well. Two out of numerous age-related cellular and molecular cerebral abnormalities attract particular attention in sporadic AD because of their functional signi®cance: (1) the state of membranes; and (2) the glucose/energy metabolism and its control. In the following, these two points will be dealt with whereby emphasis is laid on the second point. 2. Pathogenesis of sporadic AD Before addressing detailed pathogenesis, some introductory remarks on normal conditions in adulthood and during aging are presented. 2.1. State of the membrane Membranes are bilayered in structure with predominantly polyunsaturated fatty acids (FA) and cholesterol as main components. Normally, FA predominate in the exofacial
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layer as compared to cholesterol whereas it is reverse in the cytofacial layer (Igbavboa et al., 1996). This constellation maintains the distance between the two layers and, thus, the biophysical properties of membranes, i.e. normal function of ion channels, receptors, membrane-bound enzymes etc. (Spector and Yorek, 1985). Cholesterol which is intracellularly formed from acetyl CoA is the main sterol in membranes and plays an important role in cell function (Michikawa and Yanagisawa, 1999). In both, aging and sporadic AD, the proportion of saturated and unsaturated FA changes in favor of the former FA (SoÈderberg et al., 1991). Also, the concentration of cholesterol increases in the exofacial layer and decreases cytofacially (Igbavboa et al., 1996). The main membrane phospholipids lecithine and choline are catabolized (Nitsch et al., 1992a). Both, the reduction in the choline pool and in acetyl CoA (see below) may explain the enhanced selective vulnerability of the cholinergic presynapse (Wurtman, 1992). Lipid peroxidation mediated by oxidative stress (Subbarao et al., 1990) and the reduction in available energy (Wu et al., 1996) (see below) may be considered as main causes for membrane damage. A limited degree of such a damage can be handled by the cell provided the drop in available ATP is not too severe. In this case, sodium and calcium can still be exported from the cell into the extracellular space by Na 1, K 1 -ATPase and Ca 21 ATPase. However, any major damage of the membrane integrity by a permanent loss of membrane constituents is not compatible with cellular life (for review see Klein, 2000). 2.2. Glucose/energy metabolism and its control Glucose metabolism is central for the brain. Oxidation of the glycolytic endproduct pyruvate yields the energy rich compound acetyl CoA which is used for: (1) further oxidation in the tricarboxylic acid cycle to ATP; (2) the formation of the neurotransmitter acetylcholine (Gibson et al., 1975); and (3) the formation of cholesterol in the 3-hydroxy3-methylglutaryl-CoA cycle (Michikawa and Yanagisawa, 1999). As mentioned above, cholesterol is the main sterol in membranes, and it also serves as the basic compound from which neurosteroids derive (Rupprecht and Holsboer, 1999). ATP guarantees most of the cellular and molecular work such as protein synthesis, the maintenance of intra/extracellular ion homeostasis, folding, sorting, transport and degradation of proteins, the work of the endoplasmic reticulum and the Golgi apparatus, and the maintenance of synaptic transmission (for review see Hoyer, 1996, 1998). The neuronal glucose metabolism is antagonistically controlled by insulin and cortisol. Insulin is partially formed in pyramidal neurons, e.g. in the hippocampus, prefrontal cortex, entorhinal cortex and the olfactory bulb but not in glia cells. Insulin is catabolized by the insulin-degrading enzyme (Azam et al., 1990) which also degrades amyloid b protein (Kurochkin and Goto, 1994) the extracellar level of which is regulated by this enzyme in neurons (Vekrellis et al., 2000). Insulin receptors are widely distributed in the brain with highest densities in the olfactory bulb, hypothalamus, cerebral cortex and hippocampus (for details Henneberg and Hoyer, 1995; Plaschke et al., 1996). Recently, it was suggested that the insulin receptor may participate in learning processes by upregulation of the insulin receptor mRNA in the hippocampal CA1 area and dentate gyrus, and accumulation of insulin receptor protein in hippocampal synaptic membranes (Zhao et al., 1999).
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During normal aging, numerous changes at the molecular (see above) and cellular levels occur in the central nervous system (for review see Hoyer, 1995). In context with this article, the reduction of glycolysis leading to a decreased formation of acetyl CoA and energy rich phosphates, (Hoyer, 1985), the reduction of both synthesis and release of acetylcholine (Bowen, 1984), increase of presynaptic noradrenaline concentration and prolongued release of noradrenaline after stress (Harik and McCracken, 1986; Perego et al., 1993) indicating sympathetic tone, acidi®cation of the cytoplasm (Roberts and Sick, 1996), decreases of insulin concentration, of the density of insulin receptors and the tyrosine kinase (FroÈlich et al., 1998) and an increase of cortisol concentration in cerebrospinal ¯uid (Swaab et al., 1994) are of particular signi®cance. As a consequence of the derangement in neuronal glucose metabolism, advanced glycation end products are formed and deposited in neurons of brain areas which are particularly prone to degenerate in AD (Li et al., 1995). Additionally, by means of free radical mediated mixed function oxidation the intracellular protein-turnover is damaged and may start proteolysis (Stadtman, 1992). Probably, the reduced formation of acetyl CoA (see above) may give rise to a decreased formation of both cholesterol and neurosteroids by which brain functions run at a lower level than normal. It, thus, becomes obvious that aging renders the brain more vulnerable to smaller internal and external events in terms of self-organized criticality, i.e. subcriticality (Bak et al., 1988; Held et al., 1990). 2.3. Glucose/energy metabolism in sporadic Alzheimer disease In sporadic AD, an early and severe abnormality was found in cerebral glucose metabolism which aggravates with the worsening of dementia symptoms (for review see Hoyer, 1996; Hoyer et al., 1991). The abnormality in neuronal glucose metabolism is assumed to be caused by a disturbance in the control of this metabolic pathway. Although, both, the insulin concentration and the insulin receptor tyrosine kinase was not found to be different from aged-matched controls, insulin receptor density was upregulated compared to controls indicating an impairment of the insulin signal transduction cascade similar to non-insulin dependent diabetes mellitus (FroÈlich et al., 1998; Hoyer, 1998). It is as yet not clear which mechanisms may cause the desensitization of the neuronal insulin receptor. As in non-nervous tissue, cortisol and catecholamines in particular noradrenaline, may be candidates (HaÈring, 1991). Indeed, drastically enhanced levels of cortisol were found in the cerebrospinal ¯uid of sporadic Alzheimer patients (Swaab et al., 1994). Also, resting noradrenaline was found to be higher in cerebrospinal ¯uid of Alzheimer patients correlating to severity of dementia, compared to controls (Peskind et al., 1998) which obviously upregulates the cAMP-second messenger system (Martinez et al., 1999). The latter data may point to a further increase in the sympathetic tone as compared to normal aging. The pathophysiologic consequences of this dysregulation of neuronal glucose metabolism may be multifold. The diminished activity of the pyruvate dehydrogenase complex yields reduced levels of acetyl CoA (Perry et al., 1980) which is the source of the decrease of both the APOE4-independent cholesterol level (Mulder et al., 1998) and the formation of neurosteroids. The reduced activity of acetylcholine transferase in the presynaptic cholinergic neuron re¯ects the diminished availability of acetylcholine (Sims et al.,
Reduction of
Effect on
Ref.
Consequence
Ref.
Glucose
Ach synthesis +
Gibson et al., 1975
Nitsch et al., 1992
Glucose Glucose Glucose
Hoyer, 1985; Hoyer et al., 1991 Shi et al., 1997 Plee-Gautier et al., 1998
ATP
Cytoplasmic pH + Astrocytic mRNA-APP * Aspartate amino transferase gene * Protein synthesis +
Buttgereit and Brand, 1995
ATP
pH * in ER/GA
Seksek et al., 1995
ATP Insulin Insulin Insulin Insulin *
PK erk36, PK erk40 * Glycogen synthase kinase-3 * NF kappa B + NF kappa B + APP +
Roder and Ingram, 1991 Hong and Lee, 1997 Bertrand et al., 1998 Bertrand et al., 1999 Boyt et al., 2000
m1/m3 receptor stimulation + APPs + , b A4 * b A4 * APPs + NH3 * Ach-binding to synaptosomes + APPs + ; amyloidogenic derivatives * ER/GA-passage of APP + b A4(1-40) * b A4(1-42) * Tau-hyperphosphorylation Tau-hyperphosphorylation Apoptosis Mn-SOD mRNA + Probable interaction insulin /APP
Brewer, 1997 Gasparini et al., 1997 Hoyer et al., 1990; Kuriyama et al., 1968 Webster et al., 1998; Gabuzda et al., 1994 Verde et al., 1995 Gabuzda et al., 1994 Bush et al., 1995 Mandelkow et a., 1992 Grilli et al., 1996 Bertrand et al., 1999
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Table 1 Relationship between glucose/energy metabolism and Alzheimer disease-relevant cellular and molecular abnormalities
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1983). Degeneration of the cholinergic system correlates with the progress in disturbed mental capacities in Alzheimer patients (Baskin et al., 1999). Another pathophysiologic consequence of the markedly perturbed glucose metabolism is the fall of ATP production from glucose by around 50% in the beginning of sporadic AD with increasing tendency during its course (Hoyer, 1992). However, the de®cit in neuronal glucose availability may be partially balanced by the utilization of endogenous brain substrates: glucoplastic amino acids such as glutamate and fatty acids deriving from membrane phospholipids (Hoyer and Nitsch, 1989; Pettegrew et al., 1995). As a side effect of glutamate utilization, neurotoxic ammonia is formed (Hoyer et al., 1990). In spite of the above compensatory mechanisms, an energy de®cit of at least 20% is present in sporadic Alzheimer brain with increasing tendency during the course of disease. In contrast, no signi®cant drop in ATP formation could be found in early-onset AD (Hoyer, 1992) which may mean that ATP-dependent processes such as protein synthesis may not be involved in the pathogenesis of this pathological condition. Taken together, the above data clearly indicate that the disturbance of the control of the neuronal glucose/energy metabolism at the insulin/insulin receptor interaction may be central for the etiopathogenesis of sporadic AD. A cascade of abnormalities at the cellular and molecular level may be set into motion leading to the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein (Table 1). In this context, a sometimes disregarded ®nding should be stressed. The secreted form of ATP (APPs) has been shown to support neuroprotection (Mattson et al., 1993), to modulate hippocampal synaptic plasticity (Ishida et al., 1997) and to enhance memory (Meziane et al., 1998). It may be expected that these functions fail when APPs is reduced. For the formation of more probably amyloidogenic derivatives and less APPs, the following scenario is proposed. The permanent de®cit of ATP may enhance the pH in the endoplasmic reticulum/Golgi apparatus causing misfolding of APP. (Gabuzda et al., 1994; Seksek et al., 1995; Verde et al., 1995). This and the reduced availability of acetylcholine (Gibson et al., 1975) may cause an abnormal processing of APP (Nitsch et al., 1992b). In a concerted-like action tissue acidi®cation (Hoyer et al., 1990) may support this process. Since protein synthesis is reduced due to energy depletion (Buttgereit and Brand, 1995), the formation of APP may decrease resulting in a fall of APPs (Webster et al., 1998). If there were an increase in b A4 formation, this may not become obvious since the insulin-degrading enzyme also catabolizing b A4 (see above) was found to be upregulated in sporadic AD (Bernstein et al., 1999). A proportion of b A4 may escape degradation and may form neuritic plaques by advanced glycation which was found to be increased in AD (MuÈnch et al., 1998; Smith et al., 1994). Thus, no increase in b A4 concentration in the extracellular space in the brains of sporadic Alzheimer patients may be expected. Indeed, an increase of b A4 in cerebrospinal ¯uid was observed in the beginning of AD only whereas a fall in both b -amyloid 42 an 40 in the cerebrospinal ¯uid of sporadic Alzheimer patients was found in a 3-year course of the disease although the mental capacity deteriorated over this time (Nitsch et al., 1995; Tapiola et al., 2000). The data discussed so far do not support the amyloid cascade hypothesis of sporadic AD. This pathological condition may be caused by reduced neuronal activity due to the de®cit in neuronal glucose/energy metabolism (Hoyer, 1998; Swaab et al., 1998) whereby
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Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update S. Hoyer* Department of Pathochemistry and General Neurochemistry, University of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany Received 3 May 2000; received in revised form 31 May 2000; accepted 31 May 2000
Abstract It is discussed that Alzheimer disease does not form a nosologic entity. 5 to 10% of all Alzheimer cases are due to inherited abnormalities on chromosomes 1, or 14, or 21, whereas the majority of 90± 95% is sporadic in origin. Age-related changes in the composition of membranes and in glucose/ energy metabolism along with a sympathetic tone in the brain are assumed to be cellular/molecular risk factors for this disease. In its pathogenesis, the desensitization of the neuronal insulin receptor similar to non-insulin dependent diabetes mellitus may be of pivotal signi®cance. This abnormality along with a reduction in insulin concentration is assumed to induce a cascade-like process of disturbances including decreases in cellular glucose, acetylcholine, cholesterol, and ATP, associated with changes in the metabolism of amino acids and fatty acids. There is evidence that the reductions in the availability of both glucose/energy and insulin contribute to the formation of amyloidogenic derivatives and hyperphosphorylated tau protein. This may indicate that the amyloid cascade hypothesis in not valid for sporadic Alzheimer disease but that the formation of both, amyloidogenic derivatives and hyperphosphorylated tau protein is downstream the origin of this neurodegenerative disease. q 2000 Elsevier Science Inc. All rights reserved. Keywords: Alzheimer brain; Oxidative metabolism; Insulin signaling
1. Introduction Although Alzheimer disease (AD) looks rather uniform in terms of both the morphological end stage in brain and the clinical feature, there is no evidence that this neurodegenerative disorder originates by one single cause. Evidence is provided that a smaller * Tel.: 149-6221-562618; fax: 149-6221-564228. E-mail address: [email protected] (S. Hoyer). 0531-5565/00/$ - see front matter q 2000 Elsevier Science Inc. All rights reserved. PII: S 0531-556 5(00)00156-X
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Fig. 1. The nosologic heterogeneity of Alzheimer disease.
proportion of 5±10% of all Alzheimer cases is caused by genetic abnormalities on chromosomes 1, or 14, or 21 leading to early-onset AD. These different inherited disturbance serve as the basis of the amyloid cascade hypothesis of AD (Hardy, 1997; Selkoe, 1997). In contrast, the greatest proportion of all Alzheimer cases (95±90%) was found to be of late-onset and sporadic in origin. Allelic abnormalities in the APOE-gene may facultatively contribute to both anticipated onset and severity of early-onset and late-onset AD. For the latter, age-related cellular and molecular changes are considered to be risk factors (for review see Hoyer, 1995) (Fig. 1). Thus, inherited AD and sporadic AD do not form a nosologic entity. There is ®rst evidence that the aging process in the brain is accompanied by variations in gene expression as compared to adult brain in that some genes are switched on whereas other ones are switched off i.e. for cell protection (Salehi et al., 1996; Wu and Lee, 1997). Although as yet not demonstrated, such on-off-mechanisms may be assumed to be of signi®cance in the etiopathogenesis for sporadic AD as well. Two out of numerous age-related cellular and molecular cerebral abnormalities attract particular attention in sporadic AD because of their functional signi®cance: (1) the state of membranes; and (2) the glucose/energy metabolism and its control. In the following, these two points will be dealt with whereby emphasis is laid on the second point. 2. Pathogenesis of sporadic AD Before addressing detailed pathogenesis, some introductory remarks on normal conditions in adulthood and during aging are presented. 2.1. State of the membrane Membranes are bilayered in structure with predominantly polyunsaturated fatty acids (FA) and cholesterol as main components. Normally, FA predominate in the exofacial
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layer as compared to cholesterol whereas it is reverse in the cytofacial layer (Igbavboa et al., 1996). This constellation maintains the distance between the two layers and, thus, the biophysical properties of membranes, i.e. normal function of ion channels, receptors, membrane-bound enzymes etc. (Spector and Yorek, 1985). Cholesterol which is intracellularly formed from acetyl CoA is the main sterol in membranes and plays an important role in cell function (Michikawa and Yanagisawa, 1999). In both, aging and sporadic AD, the proportion of saturated and unsaturated FA changes in favor of the former FA (SoÈderberg et al., 1991). Also, the concentration of cholesterol increases in the exofacial layer and decreases cytofacially (Igbavboa et al., 1996). The main membrane phospholipids lecithine and choline are catabolized (Nitsch et al., 1992a). Both, the reduction in the choline pool and in acetyl CoA (see below) may explain the enhanced selective vulnerability of the cholinergic presynapse (Wurtman, 1992). Lipid peroxidation mediated by oxidative stress (Subbarao et al., 1990) and the reduction in available energy (Wu et al., 1996) (see below) may be considered as main causes for membrane damage. A limited degree of such a damage can be handled by the cell provided the drop in available ATP is not too severe. In this case, sodium and calcium can still be exported from the cell into the extracellular space by Na 1, K 1 -ATPase and Ca 21 ATPase. However, any major damage of the membrane integrity by a permanent loss of membrane constituents is not compatible with cellular life (for review see Klein, 2000). 2.2. Glucose/energy metabolism and its control Glucose metabolism is central for the brain. Oxidation of the glycolytic endproduct pyruvate yields the energy rich compound acetyl CoA which is used for: (1) further oxidation in the tricarboxylic acid cycle to ATP; (2) the formation of the neurotransmitter acetylcholine (Gibson et al., 1975); and (3) the formation of cholesterol in the 3-hydroxy3-methylglutaryl-CoA cycle (Michikawa and Yanagisawa, 1999). As mentioned above, cholesterol is the main sterol in membranes, and it also serves as the basic compound from which neurosteroids derive (Rupprecht and Holsboer, 1999). ATP guarantees most of the cellular and molecular work such as protein synthesis, the maintenance of intra/extracellular ion homeostasis, folding, sorting, transport and degradation of proteins, the work of the endoplasmic reticulum and the Golgi apparatus, and the maintenance of synaptic transmission (for review see Hoyer, 1996, 1998). The neuronal glucose metabolism is antagonistically controlled by insulin and cortisol. Insulin is partially formed in pyramidal neurons, e.g. in the hippocampus, prefrontal cortex, entorhinal cortex and the olfactory bulb but not in glia cells. Insulin is catabolized by the insulin-degrading enzyme (Azam et al., 1990) which also degrades amyloid b protein (Kurochkin and Goto, 1994) the extracellar level of which is regulated by this enzyme in neurons (Vekrellis et al., 2000). Insulin receptors are widely distributed in the brain with highest densities in the olfactory bulb, hypothalamus, cerebral cortex and hippocampus (for details Henneberg and Hoyer, 1995; Plaschke et al., 1996). Recently, it was suggested that the insulin receptor may participate in learning processes by upregulation of the insulin receptor mRNA in the hippocampal CA1 area and dentate gyrus, and accumulation of insulin receptor protein in hippocampal synaptic membranes (Zhao et al., 1999).
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During normal aging, numerous changes at the molecular (see above) and cellular levels occur in the central nervous system (for review see Hoyer, 1995). In context with this article, the reduction of glycolysis leading to a decreased formation of acetyl CoA and energy rich phosphates, (Hoyer, 1985), the reduction of both synthesis and release of acetylcholine (Bowen, 1984), increase of presynaptic noradrenaline concentration and prolongued release of noradrenaline after stress (Harik and McCracken, 1986; Perego et al., 1993) indicating sympathetic tone, acidi®cation of the cytoplasm (Roberts and Sick, 1996), decreases of insulin concentration, of the density of insulin receptors and the tyrosine kinase (FroÈlich et al., 1998) and an increase of cortisol concentration in cerebrospinal ¯uid (Swaab et al., 1994) are of particular signi®cance. As a consequence of the derangement in neuronal glucose metabolism, advanced glycation end products are formed and deposited in neurons of brain areas which are particularly prone to degenerate in AD (Li et al., 1995). Additionally, by means of free radical mediated mixed function oxidation the intracellular protein-turnover is damaged and may start proteolysis (Stadtman, 1992). Probably, the reduced formation of acetyl CoA (see above) may give rise to a decreased formation of both cholesterol and neurosteroids by which brain functions run at a lower level than normal. It, thus, becomes obvious that aging renders the brain more vulnerable to smaller internal and external events in terms of self-organized criticality, i.e. subcriticality (Bak et al., 1988; Held et al., 1990). 2.3. Glucose/energy metabolism in sporadic Alzheimer disease In sporadic AD, an early and severe abnormality was found in cerebral glucose metabolism which aggravates with the worsening of dementia symptoms (for review see Hoyer, 1996; Hoyer et al., 1991). The abnormality in neuronal glucose metabolism is assumed to be caused by a disturbance in the control of this metabolic pathway. Although, both, the insulin concentration and the insulin receptor tyrosine kinase was not found to be different from aged-matched controls, insulin receptor density was upregulated compared to controls indicating an impairment of the insulin signal transduction cascade similar to non-insulin dependent diabetes mellitus (FroÈlich et al., 1998; Hoyer, 1998). It is as yet not clear which mechanisms may cause the desensitization of the neuronal insulin receptor. As in non-nervous tissue, cortisol and catecholamines in particular noradrenaline, may be candidates (HaÈring, 1991). Indeed, drastically enhanced levels of cortisol were found in the cerebrospinal ¯uid of sporadic Alzheimer patients (Swaab et al., 1994). Also, resting noradrenaline was found to be higher in cerebrospinal ¯uid of Alzheimer patients correlating to severity of dementia, compared to controls (Peskind et al., 1998) which obviously upregulates the cAMP-second messenger system (Martinez et al., 1999). The latter data may point to a further increase in the sympathetic tone as compared to normal aging. The pathophysiologic consequences of this dysregulation of neuronal glucose metabolism may be multifold. The diminished activity of the pyruvate dehydrogenase complex yields reduced levels of acetyl CoA (Perry et al., 1980) which is the source of the decrease of both the APOE4-independent cholesterol level (Mulder et al., 1998) and the formation of neurosteroids. The reduced activity of acetylcholine transferase in the presynaptic cholinergic neuron re¯ects the diminished availability of acetylcholine (Sims et al.,
Reduction of
Effect on
Ref.
Consequence
Ref.
Glucose
Ach synthesis +
Gibson et al., 1975
Nitsch et al., 1992
Glucose Glucose Glucose
Hoyer, 1985; Hoyer et al., 1991 Shi et al., 1997 Plee-Gautier et al., 1998
ATP
Cytoplasmic pH + Astrocytic mRNA-APP * Aspartate amino transferase gene * Protein synthesis +
Buttgereit and Brand, 1995
ATP
pH * in ER/GA
Seksek et al., 1995
ATP Insulin Insulin Insulin Insulin *
PK erk36, PK erk40 * Glycogen synthase kinase-3 * NF kappa B + NF kappa B + APP +
Roder and Ingram, 1991 Hong and Lee, 1997 Bertrand et al., 1998 Bertrand et al., 1999 Boyt et al., 2000
m1/m3 receptor stimulation + APPs + , b A4 * b A4 * APPs + NH3 * Ach-binding to synaptosomes + APPs + ; amyloidogenic derivatives * ER/GA-passage of APP + b A4(1-40) * b A4(1-42) * Tau-hyperphosphorylation Tau-hyperphosphorylation Apoptosis Mn-SOD mRNA + Probable interaction insulin /APP
Brewer, 1997 Gasparini et al., 1997 Hoyer et al., 1990; Kuriyama et al., 1968 Webster et al., 1998; Gabuzda et al., 1994 Verde et al., 1995 Gabuzda et al., 1994 Bush et al., 1995 Mandelkow et a., 1992 Grilli et al., 1996 Bertrand et al., 1999
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Table 1 Relationship between glucose/energy metabolism and Alzheimer disease-relevant cellular and molecular abnormalities
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1983). Degeneration of the cholinergic system correlates with the progress in disturbed mental capacities in Alzheimer patients (Baskin et al., 1999). Another pathophysiologic consequence of the markedly perturbed glucose metabolism is the fall of ATP production from glucose by around 50% in the beginning of sporadic AD with increasing tendency during its course (Hoyer, 1992). However, the de®cit in neuronal glucose availability may be partially balanced by the utilization of endogenous brain substrates: glucoplastic amino acids such as glutamate and fatty acids deriving from membrane phospholipids (Hoyer and Nitsch, 1989; Pettegrew et al., 1995). As a side effect of glutamate utilization, neurotoxic ammonia is formed (Hoyer et al., 1990). In spite of the above compensatory mechanisms, an energy de®cit of at least 20% is present in sporadic Alzheimer brain with increasing tendency during the course of disease. In contrast, no signi®cant drop in ATP formation could be found in early-onset AD (Hoyer, 1992) which may mean that ATP-dependent processes such as protein synthesis may not be involved in the pathogenesis of this pathological condition. Taken together, the above data clearly indicate that the disturbance of the control of the neuronal glucose/energy metabolism at the insulin/insulin receptor interaction may be central for the etiopathogenesis of sporadic AD. A cascade of abnormalities at the cellular and molecular level may be set into motion leading to the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein (Table 1). In this context, a sometimes disregarded ®nding should be stressed. The secreted form of ATP (APPs) has been shown to support neuroprotection (Mattson et al., 1993), to modulate hippocampal synaptic plasticity (Ishida et al., 1997) and to enhance memory (Meziane et al., 1998). It may be expected that these functions fail when APPs is reduced. For the formation of more probably amyloidogenic derivatives and less APPs, the following scenario is proposed. The permanent de®cit of ATP may enhance the pH in the endoplasmic reticulum/Golgi apparatus causing misfolding of APP. (Gabuzda et al., 1994; Seksek et al., 1995; Verde et al., 1995). This and the reduced availability of acetylcholine (Gibson et al., 1975) may cause an abnormal processing of APP (Nitsch et al., 1992b). In a concerted-like action tissue acidi®cation (Hoyer et al., 1990) may support this process. Since protein synthesis is reduced due to energy depletion (Buttgereit and Brand, 1995), the formation of APP may decrease resulting in a fall of APPs (Webster et al., 1998). If there were an increase in b A4 formation, this may not become obvious since the insulin-degrading enzyme also catabolizing b A4 (see above) was found to be upregulated in sporadic AD (Bernstein et al., 1999). A proportion of b A4 may escape degradation and may form neuritic plaques by advanced glycation which was found to be increased in AD (MuÈnch et al., 1998; Smith et al., 1994). Thus, no increase in b A4 concentration in the extracellular space in the brains of sporadic Alzheimer patients may be expected. Indeed, an increase of b A4 in cerebrospinal ¯uid was observed in the beginning of AD only whereas a fall in both b -amyloid 42 an 40 in the cerebrospinal ¯uid of sporadic Alzheimer patients was found in a 3-year course of the disease although the mental capacity deteriorated over this time (Nitsch et al., 1995; Tapiola et al., 2000). The data discussed so far do not support the amyloid cascade hypothesis of sporadic AD. This pathological condition may be caused by reduced neuronal activity due to the de®cit in neuronal glucose/energy metabolism (Hoyer, 1998; Swaab et al., 1998) whereby
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the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein are downstream of the cause. However, there seems to be a close link between the perturbed activity of the insulin receptor on the one hand (see above) and both formation of b amyloid and hyperphosphorylation of tau protein on the other: cAMP enhances the processing of APP to b -amyloid (Kumar et al., 1999) and cAMP-dependent protein kinase hyperphosphorylate tau protein (Jicha et al., 1999). The pathophysiological meaning of these ®ndings for the etiopathogenesis of sporadic AD will have to be elucidated. References Azam, M., Gupta, B.L., Gupta, G., Jain, S., Baquer, N.Z., 1990. Rat brain insulin degrading enzyme in insulin and thyroid hormones imbalances. Biochem. Int. 21, 321±329. Bak, P., Tang, C., Wiesenfeld, K., 1988. Self-organized criticality. Phys. Rev. A 38, 364±374. Baskin, D.S., Browning, J.L., Pirozzolo, F.J., Korporaal, S., Baskin, J.A., Appel, S.H., 1999. Brain choline acetyltransferase and mental function in Alzheimer disease. Arch. Neurol. 56, 1123±1221. Bernstein, H.F., Ansorge, S., Riede, P., Reiser, F.M., FroÈlich, L., Bogerts, B., 1999. Insulin-degrading enzyme in Alzheimer's disease brain: prominent localization in neurons and senile plaques. Neurosci. Lett. 263, 161± 164. Bertrand, F., At®, A., Cadoret, A., L'Allemain, G., Robin, H., Lascols, O., Capeau, J., Cherqui, G., 1998. A role for nuclear factor kappa B in the antiapoptotic function of insulin. J. Biol. Chem. 273, 2931±2938. Bertrand, F., Desbois-Mouthon, C., Cadoret, A., Prunier, C., Robin, H., Capeau, J., At®, A., Cherqui, G., 1999. Insulin antiapoptic signaling involves insulin activation of the nuclear factor kappa b -dependent survival genes encoding tumor necrosis factor receptor-associated factor 2 and manganese-superoxide dismutase. J. Biol. Chem. 274, 30 596±30 602. Bowen, D.M., 1984. Cellular aging: selective vulnerability of cholinergic neurons in human brain. Monogr. Dev. Biol. 17, 42±59. Boyt, A.A., Taddei, K., Hallmayer, J., Helmerhorst, E., Gandy, S.E., Craft, S., Martins, R.N., 2000. The effect of insulin and glucose on the plasma concentration of Alzheimer's amyloid precursor protein. Neuroscience 95, 727±734. Brewer, G.J., 1997. Effects of acidosis on the distribution and processing of the b -amyloid precursor protein in cultured hippocampal neurons. Mol. Chem. Neuropathol. 31, 171±186. Bush, M.L., Niyashiro, J.S., Ingram, V.M., 1995. Activation of a neuro®lament kinase, a tau kinase and a tau phosphatase by decreased ATP levels in nerve growth factor-differentiated PC 12 cells. Proc. Natl Acad. Sci. USA 92, 1962±1965. Buttgereit, F., Brand, M.D., 1995. A hierarchy of ATP-consuming processes in mammalian cells. Biochem. J. 312, 163±167. FroÈlich, L., Blum-Degen, D., Bernstein, H.G., Engelsberger, S., Humrich, J., Laufer, S., Muschner, D., Thalheimer, A., TuÈrk, A., Hoyer, S., ZoÈchling, R., Boissl, K.W., Jellinger, K., Riederer, P., 1998. Insulin and insulin receptors in the brain in aging and sporadic Alzheimer's disease. J. Neural Transm. 105, 423±438. Gabuzda, D., Busciglio, J., Chen, L.B., Matsudaira, P., Yankner, B.A., 1994. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J. Biol. Chem. 269, 13 623±13 628. Gasparini, L., Racchi, M., Benussi, L., Curti, D., Binetti, G., Bianchetti, A., Trabucci, M., Govoni, S., 1997. Effect of energy shortage and oxidative stress in amyloid precursor protein metabolism in C0 S cells. Neurosci. Lett. 231, 113±117. Gibson, G.E., Jope, R., Blass, J.P., 1975. Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces. Biochem. J. 148, 17±23. Grilli, M., Pizzi, M., Memo, M., Spano, P.F., 1996. Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappa û activation. Science 274, 1383±1385. HaÈring, H.U., 1991. The insulin receptor: signaling mechanisms and contribution to the pathogenesis of insulin resistance. Diabetologia 34, 848±861.
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