Publications by authors named "Melita Salkovic-Petrisic"

28 Publications

  • Page 1 of 1

Is Galactose a Hormetic Sugar? An Exploratory Study of the Rat Hippocampal Redox Regulatory Network.

Mol Nutr Food Res 2021 Nov 9;65(21):e2100400. Epub 2021 Sep 9.

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.

Scope: Galactose, a ubiquitous monosaccharide with incompletely understood physiology is often exploited for inducing oxidative-stress mediated aging in animals. Recent research demonstrates that galactose can conserve cellular function during periods of starvation and prevent/alleviate cognitive deficits in a rat model of sporadic Alzheimer's disease. The present aim is to examine the acute effects of oral galactose on the redox regulatory network (RRN).

Methods And Results: Rat plasma and hippocampal RRNs are analyzed upon acute orogastric gavage of galactose (200 mg kg ). No systemic RRN disbalance is observed; however, a mild pro-oxidative shift accompanied by a paradoxical increment in tissue reductive capacity suggesting overcompensation of endogenous antioxidant systems is observed in the hippocampus. Galactose-induced increment of reductive capacity is accompanied by inflation of the hippocampal pool of nicotinamide adenine dinucleotide phosphates indicating ROS detoxification through disinhibition of the oxidative pentose phosphate pathway flux, reduced neuronal activity, and upregulation of Leloir pathway gatekeeper enzyme galactokinase-1.

Conclusion: Based on the observed findings, and in the context of previous work on galactose, a hormetic hypothesis of galactose is proposed suggesting that the protective effects may be inseparable from its pro-oxidative action at the biochemical level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mnfr.202100400DOI Listing
November 2021

Failure of the Brain Glucagon-Like Peptide-1-Mediated Control of Intestinal Redox Homeostasis in a Rat Model of Sporadic Alzheimer's Disease.

Antioxidants (Basel) 2021 Jul 13;10(7). Epub 2021 Jul 13.

Department of Pharmacology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia.

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer's disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox10071118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301063PMC
July 2021

Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses.

J Alzheimers Dis 2021 ;82(1):71-105

Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.

Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210234DOI Listing
September 2021

GLP-1 receptor - Do we really know what we're looking at?

Acta Histochem 2021 07 18;123(5):151732. Epub 2021 May 18.

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia; Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.acthis.2021.151732DOI Listing
July 2021

Additional methodological considerations regarding optimization of the dose of intracerebroventricular streptozotocin A response to: "Optimization of intracerebroventricular streptozotocin dose for the induction of neuroinflammation and memory impairments in rats" by Ghosh et al., Metab Brain Dis 2020 July 21.

Metab Brain Dis 2021 01 27;36(1):97-102. Epub 2020 Oct 27.

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.

A recent article by Ghosh et al. entitled "Optimization of intracerebroventricular streptozotocin dose for the induction of neuroinflammation and memory impairments in rats" provides an important new set of information on neuroinflammation and cognitive deficit in a rat model of sporadic Alzheimer's disease (sAD) based on intracerebroventricular administration of streptozotocin (STZ-icv) in Charles-Foster rats in the early post-treatment period of 21 days. This comment is supposed to supplement the aforementioned manuscript by providing additional perspective on important factors that should be taken into account in the process of optimization of the streptozotocin (STZ) dose for intracerebroventricular treatment, and provides a brief overview of possible sources of variation of experimental results reported by different groups working with STZ-icv rodent models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11011-020-00637-9DOI Listing
January 2021

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease.

J Neural Transm (Vienna) 2020 02 6;127(2):231-250. Epub 2020 Feb 6.

Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and co-expression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-020-02152-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035309PMC
February 2020

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice.

Neuropharmacology 2019 04 17;148:50-67. Epub 2018 Dec 17.

Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, HR-10 000, Zagreb, Croatia; Research Centre of Excellence of Fundamental, Clinical and Translational Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, HR-10 000, Zagreb, Croatia. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5- (5M) and 10- (10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid β1-42 (sAβ1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAβ1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2018.12.018DOI Listing
April 2019

Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer's disease.

Neuropharmacology 2018 06 28;135:48-62. Epub 2018 Feb 28.

Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, HR-10 000 Zagreb, Croatia; Research Centre of Excellence for Fundamental Clinical and Translational Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, HR-10 000 Zagreb, Croatia. Electronic address:

Insulin resistance and metabolic dysfunction in the brain are considered to be the pathophysiological core of sporadic Alzheimer's disease (sAD). In line with that fact, nutrients that could have therapeutic effects at this level have been investigated as possible targets in AD therapy. Galactose, an epimer of glucose, may serve as an alternative source of energy, and given orally may stimulate secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Our preliminary research indicated that oral galactose might prevent development of memory impairment in a rat model of sAD generated by intracerebroventricular administration of streptozotocin (STZ-icv). Here, we explored whether chronic oral galactose treatment could have beneficial effects on cognitive deficits already manifested at the time of initiation of galactose treatment in adult STZ-icv rats (treatment initiated 1 month after STZ-icv injection). The results clearly show that a 2-month exposure to oral galactose (200 mg/kg/day administered in a drink ad libitum) normalises impaired learning and memory functions. Memory improvement was accompanied by an improvement in brain glucose hypometabolism measured by fluorodeoxyglucose-positron emission tomography neuroimaging and by increments in active GLP-1 plasma levels as well as by an increased expression of GLP-1 receptors in the hippocampus and hypothalamus. Our findings provide strong evidence of beneficial effects of oral galactose treatment in the STZ-icv rat model of sAD and present possible underlying mechanisms including both direct effects of galactose within the brain and indirect GLP-1-induced neuroprotective effects that might open a new, dietary-based strategy in sAD treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2018.02.027DOI Listing
June 2018

The diabetic brain and cognition.

J Neural Transm (Vienna) 2017 11 1;124(11):1431-1454. Epub 2017 Aug 1.

The Center for Successful Aging with Diabetes, Endocrinology Institute, Gertner Institute, Sheba Medical Center, Epidemiology D., Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders cannot be neglected. Therefore, early diagnosis of metabolic parameters including those relevant for T2DM is required. Moreover, it is possible that therapeutic options utilized today for diabetes treatment may also have an effect on the risk for dementia. T2DM/IRBS contribute to pathological processes in AD and VaD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-017-1763-2DOI Listing
November 2017

Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer's disease?

J Neural Transm (Vienna) 2017 06 3;124(6):695-708. Epub 2017 May 3.

Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.

Accumulated evidence suggests that the insulin-resistant brain state and cerebral glucose hypometabolism might be the cause, rather than the consequence, of the neurodegeneration found in a sporadic Alzheimer's disease (sAD). We have explored whether the insulin receptor (IR) and the glucose transporter-2 (GLUT2), used here as their markers, are the early targets of intracerebroventricularly (icv) administered streptozotocin (STZ) in an STZ-icv rat model of sAD, and whether their changes are associated with the STZ-induced neuroinflammation. The expression of IR, GLUT2 and glial fibrillary acidic protein (GFAP) was measured by immunofluorescence and western blot analysis in the parietal (PC) and the temporal (TC) cortex, in the hippocampus (HPC) and the hypothalamus. One hour after the STZ-icv administration (1.5 mg/kg), the GFAP immunoreactivity was significantly increased in all four regions, thus indicating the wide spread neuroinflammation, pronounced in the PC and the HPC. Changes in the GLUT2 (increment) and the IR (decrement) expression were mild in the areas close to the site of the STZ injection/release but pronounced in the ependymal lining cells of the third ventricle, thus indicating the possible metabolic implications. These results, together with the finding of the GLUT2-IR co-expression, and also the neuronal IR expression in PC, TC and HPC, indicate that the cerebral GLUT2 and IR should be further explored as the possible sAD etiopathogenic factors. It should be further clarified whether their alterations are the effect of a direct STZ-icv toxicity or they are triggered in a response to STZ-icv induced neuroinflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-017-1727-6DOI Listing
June 2017

Translational models for vascular cognitive impairment: a review including larger species.

BMC Med 2017 01 25;15(1):16. Epub 2017 Jan 25.

Institute of Biochemistry Food and Nutrition Science, Hebrew University of Jerusalem, Rehovot, Israel.

Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited.

Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations).

Conclusions: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-017-0793-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264492PMC
January 2017

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease.

Life Sci 2015 Sep 6;136:108-19. Epub 2015 Jul 6.

Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.

Aim: Novel effective treatment is urgently needed for sporadic Alzheimer's disease (sAD). M30 ([5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline]) and HLA-20 (5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline) are brain permeable, iron chelating compounds with antioxidant activity, showing also neuroprotective activity in animal models of neurodegeneration.Weaimed to explore their therapeutic potential in non-transgenic (non-Tg) rat model of sAD developed by intracerebroventricular administration of streptozotocin (STZ-icv).

Main Methods: Therapeutic effects of chronic oral M30 (2 and 10 mg/kg) and HLA20 (5 and 10 mg/kg) treatment on cognitive impairment in STZ-icv rat model were explored by Morris Water Maze (MWM) and Passive Avoidance (PA) tests in neuropreventive and neurorescue paradigms. Data were analysed by Kruskal–Wallis and Mann–Whitney U test (p b 0.05).

Key Findings: Five-day oral pre-treatment with M30 and HLA20 dose-dependently prevented development of spatial memory impairment (MWM probe trial-time +116%/M30; +60%/HLA20) in STZ-icv rat model (p b 0.05). Eleven-week oral treatment with M30 (3×/week), initiated 8 days after STZ-icv administration dosedependently ameliorated already developed cognitive deficits in MWM test (reduced number of mistakes 3 months after the STZ-icv treatment — 59%; p b 0.05) and fully restored them in PA test (+314%; p b 0.05). Chronic M30 treatment fully restored (−47%/PHF1;−65%/AT8; p b 0.05) STZ-induced hyperphosphorylation of tau protein and normalized decreased expression of insulin degrading enzyme (+37%; p b 0.05) in hippocampus.

Significance: The results provide first evidence of therapeutic potential of M30 and HLA20 in STZ-icv rat model of sAD with underlying molecular mechanism, further supporting the important role of multi-target ironchelators in sAD treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2015.06.026DOI Listing
September 2015

Long-Term Effects of Intracerebroventricular Streptozotocin Treatment on Adult Neurogenesis in the Rat Hippocampus.

Curr Alzheimer Res 2015 ;12(8):772-84

Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Füchsleinstr. 15, D-97080 Würzburg / Germany.

Altered adult hippocampal neurogenesis (AN) plays a role in the etiopathology of Alzheimer's disease (AD), a disorder characterized by a progressive loss of memory and spatial orientation impairment. Diabetes is shown to be one risk factor for the development of the sporadic form of AD (sAD), which affects >95% of AD patients. Streptozotocin intracerebroventricularily (STZ icv) treated rats, which develop an insulin-resistant brain state and learning and memory deficits preceding amyloid beta and tau pathology, may act as an appropriate animal model for sAD. The goal of our quantitative immunohistochemistry study was to compare short-term (1 month) and long-term (3 months) effects of STZ icv treatment on different AN stages. Applying MCM2 antibodies we quantified cell (e.g. stem cell) proliferation, by the use of NeuroD and DCX antibodies we analyzed immature neurons. BrdU incorporation with approximately 27 days of survival before sacrifice allowed us to quantify and identify surviving newborn cells. Performing co-localization studies with antibodies detecting BrdU and cell-type specific markers we could confirm that STZ treatment does not affect the differentiation fate of newly generated cells. Whereas STZ icv treatment does not seem to considerably influence cell proliferation over a shortterm period (1 month), in the long-term (3 months) it significantly decreased generation of immature and mature neurons. This reduction seen after 3 months was specific for the septal hippocampus, discussed to be important for spatial learning. Moreover, AN changes display the same timeline as the development of amyloid beta pathology in this animal model of sAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1567205012666150710112147DOI Listing
July 2016

Characterization of cognitive deficits in spontaneously hypertensive rats, accompanied by brain insulin receptor dysfunction.

J Mol Psychiatry 2015 4;3(1). Epub 2015 Jun 4.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, 10 000 Zagreb, Croatia.

Background: The spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal's sex and age as well as strains used for comparison (Wistar and Wistar-Kyoto/WKY).

Methods: Three and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) β-subunit and glycogen synthase kinase-3β (GSK3β) and their phosphorylated forms were obtained via ELISA.

Results: SHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRβ-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3β ratio, as compared to WKYs.

Conclusion: Results indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40303-015-0012-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479234PMC
June 2015

Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer's disease.

J Neural Transm (Vienna) 2015 Apr 26;122(4):577-92. Epub 2015 Mar 26.

Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10000, Zagreb, Croatia.

Sporadic Alzheimer's disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ(1-42)) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ(1-42) accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ(1-42)-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-015-1394-4DOI Listing
April 2015

Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin.

Neuropharmacology 2014 Feb 18;77:68-80. Epub 2013 Sep 18.

Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité, D-14195 Berlin-Dahlem, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2013.09.002DOI Listing
February 2014

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer's disease, about the therapeutic strategies in Alzheimer's research.

J Neural Transm (Vienna) 2013 Jan 12;120(1):233-52. Epub 2012 Aug 12.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, HR 10000, Zagreb, Croatia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-012-0877-9DOI Listing
January 2013

Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer's disease: a long-term follow up study.

J Neural Transm (Vienna) 2011 May 30;118(5):765-72. Epub 2011 Apr 30.

Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-011-0651-4DOI Listing
May 2011

Dementia, diabetes, Alzheimer's disease, and insulin resistance in the brain: progress, dilemmas, new opportunities, and a hypothesis to tackle intersecting epidemics.

J Alzheimers Dis 2011 ;25(1):29-41

Department of Neurology, The University of Texas Medical Branch at Galveston, TX 77555-0539, USA.

Dementia is an increasingly prevalent condition that intersects worldwide with the epidemic of type 2 diabetes mellitus (DM2). It would seem logical to expect that the occurrence of DM2 increases the likelihood of developing dementia, due to its deleterious effect on the cerebral vasculature and the associated hormonal and metabolic changes. Many reports indicate that it also increases the risk of developing Alzheimer's disease (AD). However, other studies suggest that diabetes might have a relatively strong protective effect against AD, whereas genetically engineered animal models of the condition deteriorate more severely when there is a concomitant insulin resistant brain state (IRBS). Furthermore, IRBS alone is associated with anatomical, behavioral, and molecular changes that justify the proposal that AD may be due to an IRBS. This is explored in the context of accumulating evidence that the IRBS need not be related to peripheral insulin resistance, and that administration of insulin directly to the brain improves selected cognitive parameters targeted in AD. This view is consistent with the Damage Signals hypothesis of AD pathogenesis, which can help unifying the pleiotropic effects of agents toxic to insulin-producing/secreting (e.g., pancreatic β) cells, as well as IRBS caused by different mechanisms in AD. Such approach may help tackling the Innovation Gap, which results from a host of factors slowing down progress towards innovative palliation and prevention of AD, as well as dementia due to complications of diabetes distinct from AD, and both conditions combined with their commonly associated metabolic and hormonal alterations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-2011-101392DOI Listing
June 2012

Botulinum toxin type A reduces pain supersensitivity in experimental diabetic neuropathy: bilateral effect after unilateral injection.

Eur J Pharmacol 2010 May 1;633(1-3):10-4. Epub 2010 Feb 1.

Department of Pharmacology, University of Zagreb School of Pharmacy and Biochemistry, Zagreb, Croatia.

We investigated antinociceptive activity of botulinum toxin type A (BTX-A) in a model of diabetic neuropathic pain in rats. Male Wistar rats were made diabetic by a single intraperitoneal injection of streptozotocin (80mg/kg). Sensitivity to mechanical and thermal stimuli was measured with the paw-pressure and hot-plate test, respectively. The formalin test was used to measure sensitivity to chemical stimuli. Diabetic animals with pain thresholds lower for at least 25% compared to the non-diabetic group were considered neuropathic and were injected with BTX-A either subcutaneously (3, 5 and 7U/kg) or intrathecally (1U/kg). Mechanical and thermal sensitivity was measured at several time-points. After peripheral application, BTX-A (5 and 7U/kg) reduced mechanical and thermal hypersensitivity not only on ipsilateral, but on contralateral side, too. The antinociceptive effect started 5days following BTX-A injection and lasted at least 15days. Formalin-induced hypersensitivity in diabetic animals was abolished as well. When applied intrathecally, BTX-A (1U/kg) reduced diabetic hyperalgesia within 24h supporting the assumption of retrograde axonal transport of BTX-A from the peripheral site of injection to central nervous system. The results presented here demonstrate the long-lasting pain reduction after single BTX-A injection in the animals with diabetic neuropathy. The bilateral pain reduction after unilateral toxin application and the effectiveness of lower dose with the faster onset after the intrathecal injection suggest the involvement of the central nervous system in the antinociceptive action of BTX-A in painful diabetic neuropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2010.01.020DOI Listing
May 2010

Insulin-resistant brain state after intracerebroventricular streptozotocin injection exacerbates Alzheimer-like changes in Tg2576 AbetaPP-overexpressing mice.

J Alzheimers Dis 2010 ;19(2):691-704

Clinic of Anesthesiology, University of Heidelberg Medical School, Heidelberg, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-2010-1270DOI Listing
April 2010

Chronic exogenous corticosterone administration generates an insulin-resistant brain state in rats.

Stress 2010 Mar;13(2):123-31

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10253890903080379DOI Listing
March 2010

Single oral dose of azithromycin versus 5 days of oral erythromycin or no antibiotic in treatment of campylobacter enterocolitis in children: a prospective randomized assessor-blind study.

J Pediatr Gastroenterol Nutr 2010 Apr;50(4):404-10

University Hospital for Infectious Disease Dr. Fran Mihaljevic, Mirogojska, Croatia.

Objective: To evaluate efficacy of a single oral azithromycin dose versus standard oral erythromycin regimen or no antibiotic for Campylobacter enterocolitis in children younger than or equal to 12 years of age.

Patients And Methods: Randomized parallel group assessor-blind trial testing for inequality in efficacy between treatments was done. Patients (N = 120) were enrolled at less than or equal to 48 hours since disease onset to receive erythromycin 50 mg kg day for 5 days, single-dose azithromycin 20 mg/kg or 30 mg/kg, or no antibiotic (no treatment control) (1: 1: 1: 1). Antibiotics were commenced 8 to 10 hours after enrollment. Patients were assessed at 24-hour intervals for 6 days.

Results: In the intent-to-treat analysis, Campylobacter eradication was achieved in 20 of 30 controls and in all of the patients treated with antibiotic. Incidence of clinical cure during the observed period was 15 of 30 in the control, 14 of 30 in the erythromycin, 20 of 30 in the lower, and 25 of 30 in the higher azithromycin dose group. With adjustment for age, sex, baseline disease severity, and disease duration before enrollment, only azithromycin 30 mg/kg was superior to no treatment: incidence ratio (IR) 1.76 (95% confidence interval [CI] 1.11-2.87). It was also superior to erythromycin (IR 1.80, 97.5% CI 1.13-2.84). Regarding time to clinical cure, only azithromycin 30 mg/kg was superior to no treatment (adjusted hazard ratio [HR] 4.90, 95% CI 2.44-9.84). It was also superior to erythromycin (HR 4.17, 97.5% CI 1.91-9.09). All treatments were well tolerated.

Conclusions: The administration of single oral dose of azithromycin 30 mg/kg early after disease onset effectively eradicates the pathogen and accelerates clinical cure in childhood Campylobacter enterocolitis. It is clinically superior to an early commenced 5-day erythromycin regimen, which apparently conveys no clinically relevant benefit over no antibiotic treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0b013e3181a87104DOI Listing
April 2010

Modeling sporadic Alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities including hyperphosphorylated tau protein and amyloid-beta.

J Alzheimers Dis 2009 ;18(4):729-50

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, HR 10 000 Zagreb, Croatia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-2009-1184DOI Listing
September 2010

Reduced brain antioxidant capacity in rat models of betacytotoxic-induced experimental sporadic Alzheimer's disease and diabetes mellitus.

Neurochem Res 2007 Oct 29;32(10):1709-17. Epub 2007 Jun 29.

Department of Chemistry, Faculty of Science, University of Sarajevo, Zmaja od Bosne 35, 71 000, Sarajevo, Bosnia and Herzegovina

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-007-9410-1DOI Listing
October 2007

Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein.

J Neurochem 2007 May;101(3):757-70

Clinical Neurochemistry and National Parkinson Foundation Centre of Excellence Laboratory, Clinic for Psychiatry and Psychotherapy, Bayrische Julius-Maximilian University of Würzburg, Würzburg, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2006.04368.xDOI Listing
May 2007

Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway.

J Neurochem 2006 Feb 12;96(4):1005-15. Epub 2006 Jan 12.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

The insulin-resistant brain state is related to late-onset sporadic Alzheimer's disease, and alterations in the insulin receptor (IR) and its downstream phosphatidylinositol-3 kinase signalling pathway have been found in human brain. These findings have not been confirmed in an experimental model related to sporadic Alzheimer's disease, for example rats showing a neuronal IR deficit subsequent to intracerebroventricular (i.c.v.) treatment with streptozotocin (STZ). In this study, western blot analysis performed 1 month after i.c.v. injection of STZ showed an increase of 63% in the level of phosphorylated glycogen synthase kinase-3alpha/beta (pGSK-3alpha/beta) protein in the rat hippocampus, whereas the levels of the unphosphorylated form (GSK-3alpha/beta) and protein kinase B (Akt/PKB) remained unchanged. Three months after STZ treatment, pGSK-3alpha/beta and Akt/PKB levels tended to decrease (by 8 and 9% respectively). The changes were region specific, as a different pattern was found in frontal cortex. Structural alterations were also found, characterized by beta-amyloid peptide-like aggregates in brain capillaries of rats treated with STZ. Similar neurochemical changes and cognitive deficits were recorded in rats treated with i.c.v. 5-thio-d-glucose, a blocker of glucose transporter (GLUT)2, a transporter that is probably involved in brain glucose sensing. The IR signalling cascade alteration and its consequences in rats treated with STZ are similar to those found in humans with sporadic Alzheimer's disease, and our results suggest a role for GLUT2 in Alzheimer's pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2005.03637.xDOI Listing
February 2006
-->