alzheimers-disease

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.

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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.

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Craig LA, Hong NS, Kopp J, McDonald RJ (2008) Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress. Eur J Neurosci 27:2262-2271. doi: 10.1111/j.1460-9568.2008.06179.x

Summary: Although it is clear that loss of cholinergic neurons in the basal forebrain is intrinsic to Alzheimer’s disease, interaction of this loss with other factors in causing the disease symptoms has not been completely elucidated. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum and vertical limb of the diagonal band of Broca totaling 0.075 µg. Lesioned animals were not impaired in a water maze task, but lesioning combined with stress caused a significant reduction in performance.

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

Aztiria E, Cataudella T, Spampinato S, Leanza G (2009) Septal grafts restore cognitive abilities and amyloid precursor protein metabolism. Neurobiol Aging 30(10):1614-1625. doi: 10.1016/j.neurobiolaging.2007.12.018

Summary: Although cholinergic loss and the presence of ß-amyloid plaques are well documented in Alzheimer’s disease, it is unknown whether restoration of regulatory cholinergic inputs affects in vivo b-amyloid precursor protein (APP). 5 µg of 192-IgG-SAP (Cat. #IT-01) was split between the lateral ventricles of rats. 6 months post-surgery the animals were implanted with cholinergic-rich septal tissue grafts. Grafted animals exhibited normal or near-normal levels of APP. APP levels, as well as improved spatial navigation performance, correlated strongly with graft-induced cholinergic changes.

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

Savage S, Ogren S, Olson L, Mattsson A (2007) Immunotoxin lesion of cholinergic nucleus basalis magnocellularis neurons in Lister hooded rats impair performance in a delayed matching-to-place task. Neuroscience 2007 Abstracts 840.1/TT24. Society for Neuroscience, San Diego, CA.

Summary: Central cholinergic systems play an important role in various aspects of cognition, and deficits in cortical cholinergic function have been implicated in the cognitive impairments associated with normal aging and dementia. Cholinergic dysfunctions have also been implicated in several neuropsychiatric disorders, including schizophrenia. Though cognitive dysfunctions, such as impaired working memory, are observed in Alzheimer, as well as schizophrenic patients, the cholinergic mechanisms behind these dysfunctions are not well characterized in animal models. To investigate whether specific cortical cholinergic deficits will affect spatial learning and memory functions, we lesioned the basalo-cortical cholinergic system by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis (NBM) of adult male Lister hooded rats. Learning and memory was assessed using a delayed matching-to-place (DMP) paradigm in the water maze. We found that animals with cholinergic denervation of neocortex were impaired in the DMP-task. Thus, while the sham-operated animals rapidly learned the task without prior training, saporin-treated rats showed impairment during the initial three days of testing. By the end of the testing period, the lesioned animals had acquired the task. However, the cholinergically denervated animals showed a performance deficit throughout the duration of the experiment with higher trial latencies and longer distance traveled to find the platform as compared to the controls. They also seemed to employ a different strategy to find the hidden platform as compared to control animals. Whether the deficits after cholinergic lesions to the NBM seen in the present experiment are mnemonic and/or attentional in nature remains to be elucidated.

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

Pang K, Sinha SP, Jiao X, Servatius RJ (2007) Understanding the role of non-cholinergic medial septal neurons in learning and memory: Implications for disease- and aging-related impairments. Neuroscience 2007 Abstracts 932.22/WW17. Society for Neuroscience, San Diego, CA.

Summary: The medial septum-diagonal band of Broca (MS) has an important function in learning and memory. Furthermore, degeneration of the MS may contribute to cognitive impairments associated with Alzheimer’s disease and normal aging. Because the MS contains several types of neurons, the neuronal population(s) involved in learning and memory has been actively investigated. Animal studies have mainly focused on the cholinergic neurons that project to the hippocampus. Although complete lesions of the MS or fimbria-fornix transaction leads to spatial memory impairments, selective damage of cholinergic MS neurons produces no or a mild impairment in spatial memory, suggesting an important role of non-cholinergic neurons. Most of these non-cholinergic neurons are GABAergic. Previously, we used low concentrations of kainic acid to examine the importance of non-cholinergic MS neurons in spatial memory. However, a more selective toxin for GABAergic neurons would facilitate research, as it has done for the cholinergic system. In the present study, we use a new GABAergic immunotoxin that combines an antibody to the GABA transporter GAT1 with saporin. GAT1-saporin was administered into the medial septum of male Sprague Dawley rats. Our preliminary results show that GABAergic septohippocampal neurons as assessed by parvalbumin-immunoreactivity were virtually eliminated, while cholinergic neurons were spared in the medial septum. Current work is focused on further characterizing the cell populations affected by GAT1-saporin. Preliminary behavioral results demonstrate that GABA MS lesions did not impair spatial reference memory in the initial acquisition of a water maze task. However, a deficit was observed in reversal learning. Further testing in a procedure where the escape platform moves to a new location every day showed that rats treated with GAT1-saporin were mildly impaired in within-session learning of the new platform location. These preliminary results demonstrate that intraseptal GAT1-saporin is effective in eliminating at least some populations of GABAergic neurons in the MS. Furthermore, the preliminary behavioral results are consistent with our previous results demonstrating that damage of non-cholinergic MS neurons produces a very specific impairment on reversal learning. In summary, GAT1-saporin may be a useful tool to examine the function of GABA MS neurons in learning and memory and their contribution to cognitive impairments in disease and aging.

Related Products: GAT1-SAP (Cat. #IT-32)

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