S Hoyer

University of Pavia, Ticinum, Lombardy, Italy

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Publications (166)389.36 Total impact

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    ABSTRACT: Stroke is a leading cause of death and disability, but most of the therapeutic approaches failed in clinical trials. The energy metabolism alterations, due to marked ATP decline, are strongly related to stroke and, at present, their physiopathological roles are not fully understood. Thus, the aim of this study was to evaluate the effects of aging on ischemia-induced changes in energy mitochondrial transduction and the consequences on overall brain energy metabolism in an in vivo experimental model of complete cerebral ischemia of 15 min duration and during post-ischemic recirculation after 1, 24, 48, 72 and 96 hrs, in 1 year "adult" and 2 year-old "aged" rats. The maximum rate (Vmax) of citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase and cytochrome oxidase for electron transfer chain (ETC) were assayed in non-synaptic "free" mitochondria and in two populations of intra-synaptic mitochondria, i.e. "light" and "heavy" mitochondria. The catalytic activities of enzymes markedly differ according to: (a) mitochondrial type (non-synaptic, intra-synaptic), (b) age, (c) acute effects of ischemia and (d) post-ischemic recirculation at different times. Enzyme activities changes are injury maturation events and strictly reflect the bioenergetic state of the tissue in each specific experimental condition respect to the energy demand, as shown by the comparative evaluation of the energy-linked metabolites and substrates content. Remarkably, recovery of mitochondrial function was more difficult for intra-synaptic mitochondria in "aged" rats, but enzyme activities of energy metabolism tended to normalize in all mitochondrial populations after 96 hrs of recirculation. This observation is relevant for Therapy, indicating that mitochondrial enzymes may be important metabolic factors for the responsiveness of ischemic penumbra towards the restore of cerebral functions.
    Neurochemistry International 10/2013; · 2.66 Impact Factor
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    ABSTRACT: Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is D-galactose (the C-4-epimer of D-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD.
    Neuropharmacology 09/2013; · 4.11 Impact Factor
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    ABSTRACT: Experimental models that faithfully mimic the developmental pathology of sporadic Alzheimer's disease (sAD) in humans are important for testing the novel therapeutic approaches in sAD treatment. Widely used transgenic mice AD models have provided valuable insights into the molecular mechanisms underlying the memory decline but, due to the particular β-amyloid-related gene manipulation, they resemble the familial but not the sporadic AD form, and are, therefore, inappropriate for this purpose. In line with the recent findings of sAD being recognised as an insulin resistant brains state (IRBS), a new, non-transgenic, animal model has been proposed as a representative model of sAD, developed by intracerebroventricular application of the betacytotoxic drug streptozotocin (STZ-icv). The STZ-icv-treated animals (mostly rats and mice) develop IRBS associated with memory impairment and progressive cholinergic deficits, glucose hypometabolism, oxidative stress and neurodegeneration that share many features in common with sAD in humans. The therapeutic strategies (acetylcholinesterase inhibitors, antioxidants and many other drugs) that have been tested until now on the STZ-icv animal model have been reviewed and the comparability of the drugs' efficacy in this non-transgenic sAD model and the results from clinical trials on sAD patients, evaluated.
    Journal of Neural Transmission 08/2012; · 3.05 Impact Factor
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    ABSTRACT: Cerebral amyloid angiopathy is manifested as accumulation of amyloid β (Aβ) peptide in the wall of meningeal and cerebral arteries, arterioles and capillaries and is frequently found postmortem in sporadic Alzheimer's disease (sAD) patients. It is difficult to assess when and how cerebral amyloid angiopathy develops and progresses in humans in vivo, which is why animal AD models are used. Streptozotocin-intracerebroventricularly (STZ-icv) treated rats have been recently proposed as the model of sAD which develops insulin resistant brain state preceding Aβ pathology development. Vascular Aβ deposits in the brain of STZ-icv-treated rats (3 months old at the time of icv treatment) were visualized by Thioflavine-S staining, Congo red staining and Aβ immunohistochemistry. Thioflavine-S and Congo red staining revealed diffuse congophilic deposits in the wall of meningeal and cortical blood vessels both 6 and 9 months after the STZ-icv treatment. Preliminary Aβ1-42 and Aβ1-16 immunohistochemistry experiments showed positive staining in blood vessels 3 and 9 months after the STZ-icv treatment, respectively. Results suggest that cerebral amyloid angiopathy observed 6 and 9 months after the STZ-icv treatment seems to be a continuation and progression of the amyloid pathology observed already 3 months following the STZ-icv treatment in this non-transgenic sAD animal model.
    Journal of Neural Transmission 05/2011; 118(5):765-72. · 3.05 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2011; 7(4).
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    ABSTRACT: An insulin-resistant brain state (IRBS) was induced by intracerebroventricular application of the diabetogenic substance streptozotocin (STZ) to investigate changes in cerebral fatty acids. Six weeks after the first STZ injection, increases were found in the concentrations of palmitic and stearic acid in temporal cortex; and of palmitic acid in entorhinal cortex indicative of membrane phospholipid breakdown, and damage of the membrane structure. The relevance of these changes is discussed in relation to sporadic Alzheimer's disease.
    Journal of Neural Transmission 12/2010; 117(12):1419-22. · 3.05 Impact Factor
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    ABSTRACT: For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (AbetaPP) followed by increased amyloid-beta (Abeta) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS).We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK) alpha/beta content, and the formation of AD-like morphological hallmarks Abeta and tau protein in AbetaPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Abeta40/42 fragments, total and phosphorylated tau protein, and GSK-3alpha/beta were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Abeta fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3alpha/beta ratio (phosphorylated/total). A linear negative correlation was detected between Abeta42 and cognition, and between GSK-3alpha/beta ratio and aggregated Abeta40+42. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3alpha/beta pathway in AbetaPP-overexpressing mice.
    Journal of Alzheimer's disease: JAD 01/2010; 19(2):691-704. · 4.17 Impact Factor
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    ABSTRACT: For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (AbetaPP) followed by increased amyloid-beta (Abeta) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS). We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK)alpha/beta content, and the formation of AD-like morphological hallmarks Abeta and tau protein in AbetaPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Abeta _{40/42} fragments, total and phosphorylated tau protein, and GSK-3alpha/beta were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Abeta fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3alpha/beta ratio (phosphorylated/total). A linear negative correlation was detected between Abeta _{42} and cognition, and between GSK-3alpha/beta ratio and aggregated Abeta _{40+42} . No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3alpha/beta pathway in AbetaPP-overexpressing mice.
    Journal of Alzheimer's disease: JAD 11/2009; · 4.17 Impact Factor
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    ABSTRACT: We investigated whether long-term administration of exogenous corticosterone (CST) or vehicle as daily treatment induces changes in rat behavior and in gene expression of the rat brain insulin signaling pathway and the formation of tau protein. Two groups of male adult rats received daily subcutaneous injections of 26.8 mg/kg CST (CST stress group) or vehicle-sesame oil (injection stress group) for 60 days while the third group was taken as untreated controls (n = 8 each). Body weight and plasma CST were measured and psychometric investigations were conducted using a rat holeboard test system before and after the treatment. Gene expression analyzes were performed by RT-PCR in cerebral cortical tissue for insulin genes 1 and 2, insulin receptor (IR), insulin degrading enzyme (IDE), and tau protein. Daily injections of CST for 60 days induced a significant, 2-fold increase in rat plasma CST concentrations in comparison to untreated controls. Significantly reduced behavioral abilities in CST-treated rats were associated with reduced gene expression of insulin 1 ( - 20%), IDE ( - 23%), and IR ( - 26%), indicating an insulin-resistant brain state, followed by increased tau protein (+28%) gene expression. In summary, chronic CST administration affects gene expression in the brain IR signaling cascade and increases tau gene expression, which is associated with reductions in cognition capacity in rats.
    Stress (Amsterdam, Netherlands) 11/2009; 13(2):123-31. · 3.21 Impact Factor
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    ABSTRACT: Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-beta protein precursor derivatives amyloid-beta (Abeta(1-40) and Abeta(1-42/43) lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Abeta as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing diseases that only becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Abeta as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review.
    Journal of Alzheimer's disease: JAD 08/2009; 18(4):729-50. · 4.17 Impact Factor
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    ABSTRACT: The effect of ageing and the relationships between the catalytic properties of enzymes linked to Krebs' cycle, electron transfer chain, glutamate and aminoacid metabolism of cerebral cortex, a functional area very sensitive to both age and ischemia, were studied on mitochondria of adult and aged rats, after complete ischemia of 15 minutes duration. The maximum rate (Vmax) of the following enzyme activities: citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase as total (integrated activity of Complex I-III), rotenone sensitive (Complex I) and cytochrome oxidase (Complex IV) for electron transfer chain; glutamate dehydrogenase, glutamate-oxaloacetate-and glutamate-pyruvate transaminases for glutamate metabolism were assayed in non-synaptic, perikaryal mitochondria and in two populations of intra-synaptic mitochondria, i.e., the light and heavy mitochondrial fraction. The results indicate that in normal, steady-state cerebral cortex, the value of the same enzyme activity markedly differs according (a) to the different populations of mitochondria, i.e., non-synaptic or intra-synaptic light and heavy, (b) and respect to ageing. After 15 min of complete ischemia, the enzyme activities of mitochondria located near the nucleus (perikaryal mitochondria) and in synaptic structures (intra-synaptic mitochondria) of the cerebral tissue were substantially modified by ischemia. Non-synaptic mitochondria seem to be more affected by ischemia in adult and particularly in aged animals than the intra-synaptic light and heavy mitochondria. The observed modifications in enzyme activities reflect the metabolic state of the tissue at each specific experimental condition, as shown by comparative evaluation with respect to the content of energy-linked metabolites and substrates. The derangements in enzyme activities due to ischemia is greater in aged than in adult animals and especially the non-synaptic and the intra-synaptic light mitochondria seems to be more affected in aged animals. These data allow the hypothesis that the observed modifications of catalytic activities in non-synaptic and intra-synaptic mitochondrial enzyme systems linked to energy metabolism, amino acids and glutamate metabolism are primary responsible for the physiopathological responses of cerebral tissue to complete cerebral ischemia for 15 min duration during ageing.
    Neurochemical Research 07/2009; 34(12):2102-16. · 2.13 Impact Factor
  • P. Riederer, S. Hoyer
    Journal of The Neurological Sciences - J NEUROL SCI. 01/2009; 283(1):255-256.
  • Siegfried Hoyer, Heinrich Lannert
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    ABSTRACT: We studied the effect of long-term application of corticosterone (CORT) s.c. the equivalent of cortisol in rats, on behavior, oxidative and energy metabolism in brain parietotemporal cortex and hippocampus of 1-year-old male Wistar rats. The data were compared with results derived from long-term and low dose intracerebroventricular application of the diabetogenic drug streptozotocin (STZ) known to inhibit the function of the neuronal insulin receptor and generating an insulin resistant brain state. CORT reduced both working and reference memory increasingly with time and running parallel to the STZ-induced deficit. The effect of CORT on the activities of the glycolytic enzymes hexokinase, phosphofructokinase, pyruvate kinase, glyceraldehyde-3-phosphodehydrogenase, lactate dehydrogenase and, in tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase equaled in both experimental conditions and in both regions studied: significant decreases of all enzyme activities except lactate dehydrogenase which increased between three and fourfold of normal. The CORT- and STZ-induced marked fall in ATP was in the same range in the regions studied. Differences became obvious in the concentration of creatine phosphate in parietotemporal cerebral cortex showing no decrease after CORT obviously due to a different susceptibility of the CORT-receptor. It is discussed that both CORT and STZ may act on the neuronal insulin receptor in a similar way. However, further studies are needed on the gene expression of insulin and the insulin receptor and its protein levels to clarify the exact action of CORT on the neuronal insulin receptor function.
    Journal of Neural Transmission 10/2008; 115(9):1241-9. · 3.05 Impact Factor
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    ABSTRACT: Intracerebroventricular (icv) administration of betacytotoxic drug streptozotocin (STZ) produces long-term and progressive cognitive deficits in rats, as well as deficits in cerebral glucose and energy metabolism. These changes resemble those found in the brain of patients with sporadic Alzheimer’s disease (sAD), and therefore, STZ-icv treated rats have been proposed as an experimental model of sAD. In this study the antioxidant capacity (AC), using manual oxygen radical absorbance capacity (ORAC) assay, was measured in the rat brain frontoparietal cortex (FC) and brainstem-cerebellum region (BS-CB) after administration of STZ and another betacytotoxic drug alloxan (AL). Region-specific differences of AC were found, which were more expressed when hydroxyl radical (ORAC-OH °) generator was used in the assay. AC against ORAC-OH ° was significantly lower in BS-CB than in FC of the control rats. Furthermore, ORAC-OH ° significantly decreased in BS-CB 3-months following the icv administration of AL, but significantly increased following the TG+AL combined treatment in comparison with the controls. However, 3-months following the icv treatment of AL combination with a different glucose transport inhbitor, 3-O-methyl-D-glucose, ORAC-OH ° values in BS-CB and ORAC-ROO ° values in FC were significantly decreased in comparison to the controls. Our results suggest that betacytotoxic-icv treatment alters antioxidant defense systems in the brain, which particularly regarding the STZ-icv treatment, could be a useful tool in search for possible new antioxidant treatments of the neurodegenerative disorders such as sAD.
    Neurotoxicity Research 05/2008; 13(2):97-104. · 2.87 Impact Factor
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    ABSTRACT: Intracerebroventricular (icv) administration of betacytotoxic drug streptozotocin (STZ) produces long-term and progressive cognitive deficits in rats, as well as deficits in cerebral glucose and energy metabolism. These changes resemble those found in the brain of patients with sporadic Alzheimer's disease (sAD), and therefore, STZ-icv treated rats have been proposed as an experimental model of sAD. In this study the antioxidant capacity (AC), using manual oxygen radical absorbance capacity (ORAC) assay, was measured in the rat brain frontoparietal cortex (FC) and brainstem-cerebellum region (BS-CB) after administration of STZ and another betacytotoxic drug alloxan (AL). Region-specific differences of AC were found, which were more expressed when hydroxyl radical (ORAC(-OHo)) generator was used in the assay. AC against ORAC(-OHo) was significantly lower in BS-CB than in FC of the control rats. Furthermore, ORAC(-OHo) significantly decreased in BS-CB 3-months following the icv administration of AL, but significantly increased following the TG+AL combined treatment in comparison with the controls. However, 3-months following the icv treatment of AL combination with a different glucose transport inhbitor, 3-O-methyl-D-glucose, ORAC(-OHo) values in BS-CB and ORAC(-ROOo) values in FC were significantly decreased in comparison to the controls. Our results suggest that betacytotoxic-icv treatment alters antioxidant defense systems in the brain, which particularly regarding the STZ-icv treatment, could be a useful tool in search for possible new antioxidant treatments of the neurodegenerative disorders such as sAD.
    Neurotoxicity Research 05/2008; 13(2):97-104. · 2.87 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2008; 4(4).
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    ABSTRACT: It is believed that oxidative stress plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer’s disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity against peroxyl (ORAC_roo ) and hydroxyl (ORAC_oh ) free radical was measured in three different brain regions (hippocampus, cerebellum, and brain stem) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased antioxidant capacity has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy. Also, these abnormalities were not prevented by the icv pretreatment of glucose transport inhibitor 5-thio-D-glucose in the STZ-icv treated rats, suggesting different mechanism for STZ-induced central effects from those at the periphery. Similarities in the oxidative stress alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for new drugs in the treatment of sAD that have antioxidant activity.
    12/2007: pages 235-240;
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    ABSTRACT: It is believed that oxidative stress (OS) plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer's disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity (AC) against peroxyl (ORAC(-ROO) (*)) and hydroxyl (ORAC(-OH) (*)) free radicals (FR) was measured in three different brain regions: the hippocampus (HPC), the cerebellum (CB), and the brain stem (BS) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased AC has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy (PDN). Also, these abnormalities were not prevented by the intracerebroventricularly (icv) pretreatment of glucose transport inhibitor 5-thio-D: -glucose (TG) in the STZ-icv treated rats, suggesting different mechanism of STZ-induced central effects from those at the periphery. Similarities of the OS alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for the new drugs in the treatment of sAD that have antioxidant activity. In the STZ-induced diabetic animals the existence of PDN was tested by the paw pressure test, 3 weeks following the diabetes induction. Mechanical nociceptive thresholds were measured three times at 10-min intervals by applying increased pressure to the hind paw until the paw-withdrawal or overt struggling was elicited. Only those diabetic animals which demonstrated decreased withdrawal threshold values in comparison with the control non-diabetic animals (C) were considered to have developed the PDN.
    Neurochemical Research 11/2007; 32(10):1709-17. · 2.13 Impact Factor
  • S. Hoyer, L. Frölich
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    ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD) are the predominant neurodegenerative disorders of late life. Both disorders do not form nosological entities. A minority of all AD cases is caused by mutations on chromosomes 1, 14 and 21, a minority of all PD cases by mutations on chromosomes 1, 2, 4, 6 and 12, whereas the majority of all both AD and PD cases is age‐related and sporadic in origin. In sporadic AD, the desensitization of the neural insulin receptor similar to non‐insulin dependent diabetes mellitus may be the core abnormality inducing a cascade‐like process of disturbances in the insulinergic, acetylcholinergic and glutamatergic systems. Cellular glucose metabolism and its derivatives acetylcholine, cholesterol and ATP are most compromised probably inducing abnormalities in the metabolism of the amyloid precursor protein APP and of tau‐protein resulting in the formation of both amyloidiogenic derivatives and hyperphosphorylated tau‐protein. As a result, mental deficits in cognition, learning and memory predominate the clinical feature. Although mental deficits are also found in the course of PD due to an involvement of the acetylcholinergic system, this disorder starts with movement disturbances due to structural and metabolic abnormalities of nigrostriatal dopaminergic system. Thus, clear differences become obvious between sporadic AO and sporadic PD in their pathophysiologies.
    08/2007: pages 189-232;
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    ABSTRACT: The intracerebroventricular (icv) application of streptozotocin (STZ) in low dosage was used in 3-month-old rats to explore brain insulin system dysfunction. Three months following STZ icv treatment, the expression of insulin-1 and -2 mRNA was significantly reduced to 11% in hippocampus and to 28% in frontoparietal cerebral cortex, respectively. Insulin receptor (IR) mRNA expression decreased significantly in frontoparietal cerebral cortex and hippocampus (16% and 33% of control). At the protein/activity level, different abnormalities of protein tyrosine kinase activity (increase in hippocampus), total IR beta-subunit (decrease in hypothalamus) and phosphorylated IR tyrosine residues (increase) became apparent. The STZ-induced disturbance in learning and memory capacities was not abolished by icv application of glucose transport inhibitors known to prevent STZ-induced diabetes mellitus. The discrepancy between reduced IR gene expression and increase in both phosphorylated IR tyrosine residues/protein tyrosine kinase activity may indicate imbalance between phosphorylation/dephosphorylation of the IR beta-subunit causing its dysfunction. These abnormalities may point to a complex brain insulin system dysfunction after STZ icv application, which may lead to an increase in hyperphosphorylated tau-protein concentration. Brain insulin system dysfunction is discussed as possible pathological core in the generation of hyperphosphorylated tau protein as a morphological marker of sporadic Alzheimer's disease.
    Journal of Neurochemistry 06/2007; 101(3):757-70. · 3.97 Impact Factor

Publication Stats

3k Citations
389.36 Total Impact Points

Institutions

  • 2002–2013
    • University of Pavia
      • Department of Molecular Medicine
      Ticinum, Lombardy, Italy
    • Cornell University
      • Department of Neurology and Neuroscience
      Ithaca, NY, United States
  • 1968–2013
    • Universität Heidelberg
      • • Department of Pathology
      • • University Hospital of Anaesthesiology
      • • Institute of Pathology (Mannheim)
      • • Department of Psychiatry and Psychotherapy
      Heidelburg, Baden-Württemberg, Germany
  • 2005–2012
    • University of Zagreb
      • • School of Medicine (MEF)
      • • Department of Pharmacology
      Zagreb, Grad Zagreb, Croatia
  • 2007–2008
    • University of Sarajevo
      Bosna-Sarai, Federation of Bosnia and Herzegovina, Bosnia and Herzegovina
  • 1990–2007
    • University of Wuerzburg
      • • Department of Psychiatry, Psychosomatics, and Psychotherapy
      • • Institute of Organic Chemistry
      Würzburg, Bavaria, Germany
  • 1995–2006
    • Goethe-Universität Frankfurt am Main
      • Klinik für Psychiatrie, Psychosomatik und Psychotherapie
      Frankfurt am Main, Hesse, Germany
  • 1994
    • Heidelberg University
      Tiffin, Ohio, United States
  • 1992
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany