alzheimers-disease

Szot P, Franklin A, White S, Raskind M (2010) Time- and dose-response of 6-hydroxydopamine on locus coeruleus noradrenegric neurons in c57bl/6 mice. Neuroscience 2010 Abstracts 157.20/R1. Society for Neuroscience, San Diego, CA.

Summary: Locus coeruleus (LC) noradrenergic neurons are severely reduced in Alzheimer’s and Parkinson’s disease. However, it is unclear why these neurons are lost and the consequence of this loss on the progression and symptoms of these neurodegenerative disorders. Therefore, establishing an animal model of LC noradrenergic neuronal loss is critical in determining how the LC contributes to these disorders. The purpose of this study was to determine the dose- and time-response of noradrenergic neurotoxicity of 6-hydroydopamine (6OHDA) in adult male C57BL/6 mice. Our laboratory recently demonstrated that DSP4 does not result in a loss of LC noradrenergic neurons. Neurotoxicity of 6OHDA on LC noradrenergic neurons was determined by measuring tyrosine hydroxylase (TH) mRNA expression and TH-immunoreactivity (IR) in LC noradrenergic neurons. TH mRNA was quantitated using MCID (OD), while TH-IR was used to determine if protein levels reflected what was observed with mRNA. 6OHDA (20 µg/µl bilaterally) and dopamine beta-hydroxylase-saporin (DBH-saporin; 1 µg/µl bilaterally) were initially administered into the lateral ventricles (icv) and sacrificed 2 weeks later. 6OHDA reduced TH mRNA and -IR in both the dopaminergic neurons of the substantia nigra (SNpc) and ventral tegmental nucleus (VTA), and LC by -46%, -65% and -63%, respectively. DBH-saporin icv injection did not affect dopaminergic or noradrenergic neurons. Injection of DBH-saporin into the LC (0.1 µg/µl unilaterally) also did not affect LC noradrenergic neurons 2 weeks later. As a time-course 6OHDA (7 µg/µl) was injected unilaterally into the LC (vehicle was administered in the alternate LC) and sacrificed 3 days, 2 and 3 weeks later. A loss of LC noradrenergic neurons was observed only 3 weeks later (-81.4%). 6OHDA was then injected unilaterally into the LC at 7, 10, and 14 ug/ul (vehicle was administered in the alternate LC) and sacrificed 2 weeks later. The 7 µg/µl dose of 6OHDA did not affect TH mRNA in the LC as compared to control side (-19%), 10 ug/ul 6OHDA significantly reduced TH mRNA in the LC by ~55%, and 14 ug/ul 6OHDA dramatically reduced TH mRNA in the LC by ~90%. TH-IR in the LC of the three different 6OHDA doses reflected closely the TH mRNA data. 6OHDA at the dose of 14 µg/µl, which resulted in a near complete loss of LC noradrenergic neurons, did not affect dopaminergic neurons in the SN (-9%) and VTA (+17%). These data indicate that DBH-saporin, at the parameters studied, did not affect mouse LC noradrenergic neurons. 6OHDA demonstrated a time- and dose-response reduction of mouse LC noradrenergic neurons. The consequence of this LC neuronal loss on forebrain noradrenergic markers will also be presented.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Klinkenberg I, Blokland A (2010) The validity of scopolamine as a pharmacological model for cognitive impairment: A review of animal behavioral studies. Neurosci Biobehav Rev 34(8):1307-1350. doi: 10.1016/j.neubiorev.2010.04.001 PMID: 20398692

Objective: To provide an overview is given of the effects of scopolamine on animal behavior.

Summary: The most important and influential articles over the past 40 years are included in the present review. The cholinergic hypothesis of memory function as originally put forward by Bartus et al. (1982) has undergone a revision after several lesion studies were performed which used the highly specific cholinergic toxin 192 IgG-SAP (Wiley et al., 1995).

Related Products: 192-IgG-SAP (Cat. #IT-01)

See Also:

• Chudasama Y et al. Cholinergic modulation of visual attention and working memory: Dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine. Learn Mem 11(1):78-86, 2004.
• Wiley RG et al. Destruction of the cholinergic basal forebrain using immunotoxin to rat NGF receptor: modeling the cholinergic degeneration of Alzheimer’s disease. J Neurol Sci 128:157-166, 1995.
• Wiley RG et al. Immunolesioning: Selective destruction of neurons using immunotoxin to rat NGF receptor. Brain Res 562:149-153, 1991.
• Wrenn CC et al. The behavioral functions of the cholinergic basal forebrain: lessons from 192 IgG-saporin. Int J Dev Neurosci 16(7-8):595-602, 1998.
• Wenk GL The nucleus basalis magnocellularis cholinergic system: one hundred years of progress. Neurobiol Learn Mem 67(2):85-95, 1997.
• Baxter MG et al. Intact spatial learning in both young and aged rats following selective removal of hippocampal cholinergic input. Behav Neurosci 110:460-467, 1996.
• Baxter MG et al. Intact spatial learning in both young and aged rats following selective removal of hippocampal cholinergic input. Behav Neurosci 110:460-467, 1996.
• Baxter MG et al. Disruption of decrements in conditioned stimulus processing by selective removal of hippocampal cholinergic input. J Neurosci 17:5230-5236, 1997.
• Chiba AA et al. Selective removal of cholinergic neurons in the basal forebrain alters cued target detection. Neuroreport 10(14):3119-3123, 1999.
• McGaughy J et al. Effects of chlordiazepoxide and scopolamine, but not aging, on the detection and identification of conditional visual stimuli. J Gerontol A Biol Sci Med Sci 50(2):B90-B96, 1995.
• McGaughy J et al. Crossmodal divided attention in rats: effects of chlordiazepoxide and scopolamine. Psychopharmacology (Berl) 115(1-2):213-220, 1994.
• Torres EM et al. Behavioral, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system. Neuroscience 63:95-122, 1994.
• Voytko ML Cognitive functions of the basal forebrain cholinergic system in monkeys: memory or attention?. Behav Brain Res 75(1-2):13-25, 1996.

De Bartolo P, Cutuli D, Ricceri L, Gelfo F, Foti F, Laricchiuta D, Scattoni ML, Calamandrei G, Petrosini L (2010) Does age matter? Behavioral and neuro-anatomical effects of neonatal and adult basal forebrain cholinergic lesions. J Alzheimers Dis 20:207-227. doi: 10.3233/JAD-2010-1355 PMID: 20164586

Summary: The authors characterized the differences caused by age on the effect of cholinergic lesions of the basal forebrain. Seven-day-old rats received 210 ng bilateral intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01). Eighty-day-old rats received 4 µg bilateral intracerebroventricular injections of 192-IgG-SP. Both experimental groups displayed similar behavior, indicating that development of a depleted cholinergic system yields similar results to cholinergic dysfunction in adulthood.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Gibbs RB (2010) Estrogen therapy and cognition: a review of the cholinergic hypothesis. Endocr Rev 31(2):224-253. doi: 10.1210/er.2009-0036

Summary: This review discusses estrogen therapy for use in postmenopausal women. In this context the issues revolve around benefits vs. harm of such therapy on the brain and cognitive impairment associated with aging and Alzheimer’s disease. Use of 192-IgG-SAP (Cat. #IT-01) to investigate this paradigm is described.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Rennie KE, Ward C, Fréchette M, Pappas BA (2009) Effects of combined neonatal cholinergic lesion and chronic cerebral hypoperfusion on CA1 cytoarchitecture. Neuroscience 2009 Abstracts 736.23/M38. Society for Neuroscience, Chicago, IL.

Summary: Neonatal lesioning of the basal forebrain cholinergic (BFC) system alters cytoarchitecture of pyramidal cells in both the hippocampus and neocortex of the adult rat, indicating a role for the BFC in forebrain development. In addition to altering forebrain development, neonatal cholinergic lesion may also exacerbate the brain’s response to pathological factors that emerge as the brain ages. One factor that might interact with BFC lesion is reduced cerebral blood flow (hypoperfusion). Examining this interaction is especially interesting because both BFC degeneration and reduced cerebral blood flow are characteristics of Alzheimer’s disease. In the rat, chronic cerebrovascular insufficiency by itself reportedly causes the degeneration of hippocampal CA1 pyramidal cells, alters amyloid processing and produces spatial memory impairments. We hypothesized that neonatal cholinergic lesion using the cholinotoxin 192-IgG-saporin would render the hippocampus more vulnerable to the neuropathological effects of chronic forebrain hypoperfusion induced by permanent bilateral occlusion of the carotid arteries (2VO). We previously reported that combined BFC lesion and 2VO impaired working memory in the Morris water maze and increased anxiety-like behaviours on the elevated plus apparatus, whereas neither of these treatments alone caused any of these effects. Here we report the effects of neonatal BFC lesion, 2VO, or their combined application on hippocampal CA1 cytoarchitecture using quantitative Golgi analysis. Rats subjected to 2VO showed increased apical branch length and spines, and increased basal spines. Neonatal BFC lesion on its own had only restricted effects on apical branch length at certain branch orders and no effect on spines. However, at a number of branch orders the stimulating effect of 2VO on apical spines occurred only in animals subjected to neonatal BFC lesion, indicating that this lesion modulated the response to 2VO. To our knowledge, this is the first examination of the effects of 2VO on CA1 neuron cytoarchitecture. Surprisingly, it increased rather than decreased dendritic length and spines. Furthermore, while the BFC lesion had minimal effects on its own, it was permissive to some of the effects of 2VO on dendritic spines. Taken together with our previous data, this study suggests that pre-existing cholinergic dysfunction alters aspects of both the behavioural and neural consequences of chronic hypoperfusion. These results may have implications for Alzheimer’s disease where cholinergic dysfunction and hypoperfusion are co-expressed

Related Products: 192-IgG-SAP (Cat. #IT-01)

Jeong D, Hwang Y, Lee D, Chang J (2009) Behavioral and histological characteristics of 192 IgG-saporin injected rats depending on injection site and dose. Neuroscience 2009 Abstracts 526.23/H8. Society for Neuroscience, Chicago, IL.

Summary: Cholinergic neuronal deficits are evident in both Alzheimer’s disease dementia (AD) and vascular dementia (VaD). Forebrain Cholinergic neurons in the nucleus basalis magnocellularis (NBM) project primarily to the neocortex, and those in the medial septum project to the hippocampus and they make an important role in memory function. We used 192 IgG-saporin to mimic deficits of cholinergic neurons at AD and VaD. 192 IgG-saporin is composed with monoclonal antibody had a low affinity to the rat nerve growth factor receptor p75 and ribosomal inactivating protein, called saporin. When injected intracerebroventricularly or directly into the basal forebrain cholinergic complex, 192 IgG-saporin selectively destroys cholinergic neurons. Many experimenters had used 192 IgG-saporin to investigate cholinergic function but it had been used in different doses and sites of lesion. This makes it difficult to compare the degrees of impairment produced by different lesions. Consequently, our aim is observation of behavioral and histological changes depending on injection site and dose of 192 IgG-saporin. We injected 192 IgG-saporin (0.63ug/ul) in medial septum (dose: 0.05ul, 0.1ul, 0.2ul) or lateral ventricle (dose: 6ul, 8ul, 10ul). 192 IgG-saporin injected rats were compared with Dulbecco’s phosphate buffered saline injected rats. Neurological deficit and functional outcome were determined by immuohistochemistry using anti-cholineacetyltransferase antibody and behavioral test, called water maze. In immunohistological study, the extent of the cholinergic lesion was showed in the basal forebrain complex region of 8ul and 10ul of 192 IgG-saporin injected rats. In behavioral study, sham and lesion groups were able to learn the reference aspect of the water maze within 5day of training. In probe test, we observed significant decrease in time in target quadrant, platform and platform crossings, and increase in latency to first crossing at 8ul and 10ul of 192 IgG-sapoin injected rats (p<0.05). Therefore, our study evaluated that 8ul 192 IgG-saporin injections were sufficient to make an AD mimic dementia model.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Matchynski JJ, Lowrance S, Rossignol J, Puckett N, Derkorver N, Radwan J, Trainor K, Sandstrom M, Dunbar G (2009) Intracerebroventricular injections of mu-P-75 saporin can produce memory deficits without impairing motor deficits in a mouse model of Alzheimer’s disease. Neuroscience 2009 Abstracts 528.1/H34. Society for Neuroscience, Chicago, IL.

Summary: Intracerebroventricular injections of mu-P-75 saporin (Advanced Targeting Systems, San Diego, CA) effectively and efficiently destroys cholinergic neurons and creates memory deficits in mice, mimicking some of the key symptoms of Alzheimer’s disease. Early attempts to use mu-P-75 saporin in mice required a relatively high mean effective dose (ED50) of 3.6 µg in order to create behavioral deficits (Berger-Sweeney et al., 2001, The Journal of Neuroscience, 21: 8164-8173; Hunter et al, 2004, European Journal of Neuroscience, 19: 3305-3316). Recent advances in producing the saporin have lowered the ED50 to doses to 0.4 µg, although the resulting memory deficits are transient, and doses above 0.8 µg can cause motor deficits (Moreau et al., 2008, Hippocampus, 18: 610-622). In an effort to elucidate the behavioral effects of a higher (0.8 µg) dose, we gave bilateral intracerbroventricular injections of mu-P-75 saporin (n=6) or sterile phosphate buffered saline (n=3) into C57/BL6 mice and assessed their cognitive abilities on both a Morris water maze (MWM) and an object-recognition task, while monitoring their motor abilities using a rotarod task. Mice receiving the mu-P-75 saporin performed significantly worse than sham animals on an object recognition task and tended to have longer latencies and swim paths during the seven days of MWM testing. Importantly, no between-group differences were observed for latency to fall on the rotarod task. Collectively, these results suggest that the 0.8 µg dose of saporin is both safe and effective for mimicking AD-like memory deficits, without causing significant motor deficits.

Related Products: mu p75-SAP (Cat. #IT-16)

Lima T-Z, Blanco MM, Bueno MA, Dos Santos Junior JG, Bargieri DY, Mello LE (2009) The influence of cholinergic degeneration on the progression of Alzheimer’s disease and its action in determining the outcome of lithium treatment. Neuroscience 2009 Abstracts 139.26/D36. Society for Neuroscience, Chicago, IL.

Summary: A substantial loss of cholinergic innervation in the hippocampus and cerebral cortex is universally accepted as a typical feature of Alzheimer’s disease (AD). Cholinergic deafferentation is an often, but not a constant phenomenon in AD and its contribution to the progression of disease is not completely understood. The present work was aimed to evaluate the effect of cholinergic deafferentation on cognitive decline and on Amyloid-b (A_) metabolism and how this outcome is modulated by lithium. To this end rats were subjected to neonatal intracerebroventricular injection of 192 IgG-saporin (an immunotoxin selective to cholinergic neurons). Three months after surgery animals were evaluated in Morris Water Maze (MWM) and then entered a three months long lithium (LiCl) or control treatment. At the end of treatment, animals were once again tested in MWM and their cerebral cortical A_ levels were measured. We found that working memory impairment arises earlier and it is also more severe than reference memory related deficits. The cognitive performance was only slightly influenced by LiCl treatment. Furthermore we found that the cholinergic denervation produced by neonatal IgG-sap infusion did not modify A_ levels or its aggregation state. Moreover lithium increased the levels of A_1-42 despite decreasing the amount of A_1-40, an effect that is dependent of cholinergic integrity. These data suggest that the contribution of cholinergic deafferentation, which occurs over the progression of disease, to the amyloigenesis is likely to be modest in AD brain. In addition the effects of lithium treatment presented here imply in avoiding its use as prophylactic propose for AD and in AD cases without marked cholinergic degeneration.

Related Products: 192-IgG-SAP (Cat. #IT-01)

De Bartolo P, Gelfo F, Mandolesi L, Foti F, Cutuli D, Petrosini L (2009) Effects of chronic donepezil treatment and cholinergic deafferentation on parietal pyramidal neuron morphology. J Alzheimers Dis 17:177-191. doi: 10.3233/JAD-2009-1035 PMID: 19494441

Summary: Donepezil has been shown to enhance cognitive functioning in both healthy patients and those suffering from dementia. This study examined whether donepezil treatment changes neocortical morphology in healthy or diseased brains. Rats received 4 µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricles. Various morphological parameters were analyzed demonstrating that in the absence of cholinergic neurons donepezil prevented the compensatory response rather than enhanced function.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Craig LA, Hong NS, Kopp J, McDonald RJ (2009) Cholinergic depletion of the medial septum followed by phase shifting does not impair memory or rest-activity rhythms measured under standard light/dark conditions in rats. Brain Res Bull 79(1):53-62. doi: 10.1016/j.brainresbull.2008.10.013

Summary: It has been theorized that cognitive decline observed in Alzheimer’s disease is in part due to disruption of the circadian rhythm (CR) in these patients. Some basal forebrain cholinergic neurons project to the suprachiasmatic nucleus, which is responsible for maintenance of CR. Rats received two injections totaling 7.5 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum/diagonal band of Broca. Lesioned animals did not show any evidence of CR disruption.

Related Products: 192-IgG-SAP (Cat. #IT-01)