alzheimers-disease

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.

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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)

Antonini V, Prezzavento O, Coradazzi M, Marrazzo A, Ronsisvalle S, Arena E, Leanza G (2009) Anti-amnesic properties of (+/-)-PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats. J Neurochem 109:744-754. doi: 10.1111/j.1471-4159.2009.06000.x

Summary: Sigma-1 receptors are found throughout the central nervous system, and are thought to be a target for regenerative therapy in Alzheimer’s disease. Rats received 3.0 µg or 5.0 µg of 192-IgG-SAP (Cat. #IT-01) injected intracerebroventricularly. The lesioned animals displayed dose-dependent deficits in water maze performance. Treatment with the sigma-1 receptor agonist (±)-PPCC significantly improved both reference and working memory performance in treated animals, indicating that (±)-PPCC-mediated positive effects are probably a function of the sigma-1 receptor.

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

Cutuli D, Foti F, Mandolesi L, De Bartolo P, Gelfo F, Federico F, Petrosini L (2009) Cognitive performances of cholinergically depleted rats following chronic donepezil administration. J Alzheimers Dis 17(1):161-176. doi: 10.3233/JAD-2009-1040 PMID: 19221411

Summary: The authors examined whether donepezil could improve cognitive functions in rats with lesions of the cholinergic cells in the forebrain. Treated animals received 4 µg bilateral intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01), followed by treatment with donepezil or a control. Donepezil-treated animals performed significantly better than control animals.

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

Martin MM, Weathered SL, Wagner SJ, Wallace DG (2008) Galanthamine does not attenuate attentional or temporal impairments subsequent to cholinergic deafferentation of the cortex or hippocampus. Neuroscience 2008 Abstracts 441.12/T4. Society for Neuroscience, Washington, DC.

Summary: The role of the basal forebrain cholinergic system in early symptomology of dementia of the Alzheimer’s type (DAT) remains an area of intense debate. Although involvement of the basalocortical cholinergic system in attentional processing has been established, function of the septohippocampal cholinergic system remains to be determined. A recent study demonstrated a double dissociation between these systems in the organization of rat food protection behavior that may parallel the attentional impairments and temporal disorientation observed during the early stages of DAT. The current study sought to examine whether an acetylcholinesterase inhibitor currently used for the treatment of DAT (i.e., galanthamine) could attenuate these deficits. Consistent with previous research, intraparenchymal injections of 192 IgG-Saporin into the nucleus basalis or medial septum area in female Long Evans rats produced dissociable effects on the organization of food protection behavior. Specifically, nucleus basalis lesions selectively reduced the number of successful food protection behaviors; whereas, medial septum lesions selectively disrupted the temporal organization of food protection behavior. These impairments were not attenuated by the administration of 3 mg/kg s.c. galanthamine twice daily. Results of this study suggest that the modest benefits afforded by galanthamine administration in DAT patients may not reflect improved attention or temporal orientation. Continued studies aimed at understanding the neural dysfunction underlying these deficits may lead to the development of novel therapeutic agents for DAT.

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

Craig LA, Hong NS, Kopp J, McDonald RJ (2009) Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats. Exp Brain Res 193(1):29-42. doi: 10.1007/s00221-008-1592-5

Summary: Recent work has suggested that reduced levels of acetylcholine, seen in Alzheimer’s disease patients, increases the susceptibility of hippocampal neurons to future challenges. Rats received two injections totaling 7.5 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band of Broca. The vasoconstrictor endothelin-1 was used to create small localized strokes in the hippocampus of lesioned animals. The data suggest that loss of these hippocampal neurons compromises functional recovery from stroke.

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

Mandolesi L, De Bartolo P, Foti F, Gelfo F, Federico F, Leggio MG, Petrosini L (2008) Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion. J Alzheimers Dis 15:11-28. doi: 10.3233/jad-2008-15102 PMID: 18780964

Summary: The cognitive reserve model suggests individuals can develop resources that reduce the risk of later cognitive impairment. This theory was tested by raising rats in standard vs. enriched environments then lesioning the animals with 192-IgG-SAP (Cat. #IT-01). A total of 0.8 µg of 192-IgG-SAP was administered in bilateral injections, followed by various behavioral tests. It was found that animals raised in an enriched environment had reduced cognitive impairment following forebrain lesions.

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

Craig LA, Hong NS, Kopp J, McDonald RJ (2008) Reduced cholinergic status in hippocampus produces spatial memory deficits when combined with kainic acid induced seizures. Hippocampus 18(11):1112-1121. doi: 10.1002/hipo.20471

Summary: The loss of cholinergic neurons in the medial septum and seizures are both associated with Alzheimer’s disease. The authors investigated links between these factors using 192-IgG-SAP (Cat. #IT-01) and kainic acid. Rats received 0.15 µg of 192-IgG-SAP delivered to the medial septum and vertical limb of the diagonal band of Broca in four injections. Animals receiving both 192-IgG-SAP and kainic acid performed significantly worse in water maze tests than control animals, indicating that loss of cholinergic neurons and seizures interact in Alzheimer’s disease.

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