alzheimers-disease

Perry T, Hodges H, Gray JA (2001) Behavioural, histological and immunocytochemical consequences following 192 IgG-Saporin immunolesions of the basal forebrain cholinergic system. Brain Res Bull 54(1):29-48. doi: 10.1016/s0361-9230(00)00413-5

Summary: 192-Saporin (Cat. #IT-01) has been used extensively as a model for Alzheimer’s Disease. The neuronal deficits caused by intraparenchymal forebrain injections (0.3-0.51 µg/µl) are apparent during tasks demanding attentional processing, but not standard tasks of learning and memory. Perry et al. compare the testing strategies for each deficit. They find that the water maze may not demand enough attentional processing to demonstrate deficits caused by this lesion. The authors also study long-term effects of 192-Saporin in rats. Although the authors produced very useful data at five to six months, they found evidence of an inflammatory response and non-specific cell death eleven months post treatment, indicating 192-Saporin may be problematic for very long-term experiments.

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Villa AEP, Tetko IV, Dutoit P, Vantini G (2000) Non-linear cortico-cortical interactions modulated by cholinergic afferences from the rat basal forebrain. BioSystems 58:219-228. doi: 10.1016/s0303-2647(00)00126-x

Summary: Elimination of the cholinergic neurons of the basal forebrain (BF) is an excellent model for some aspects of Alzheimer’s Disease (AD). 192-Saporin (Cat. #IT-01) is a very effective tool for elimination of cholinergic neurons in the BF. Villa et al. investigate whether field potential changes in the brains of lesioned animals mimic changes observed in the brains of human AD patients. The data presented indicate depletion of cholinergic neurons from the BF of both rats and humans produces similar changes in field potential.

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Westhead C, Saari RK, Morrison P, Williams PT, Saari MJ (2000) Nucleus basalis magnocellularis and enriched housing: Partners in neural patterns of attention?. Neuroscience 2000 Abstracts 837.3. Society for Neuroscience, New Orleans, LA.

Summary: Diminished levels of cholinergic markers in the brains of Alzheimer’s patients led to the belief that central cholinergic systems play a major role in cognitive processes including attention and memory. Recent evidence from our laboratory suggests that housing rats in a complex environment alters neuronal attentional circuitry. These findings led to the design of the current experiment. After weaning, groups of female Wistar rats received either a bilateral infusion of 192-IgG saporin or vehicle solution into the basal forebrain. Following recovery, rats were either housed in an enriched condition or in isolated housing for two weeks, thus creating four treatment groups. Open field testing revealed the expected Housing by Minute interaction but no lesion related effects. The rats were also tested in an incidental learning paradigm. Briefly, half of the rats were pre-exposed to the testing apparatus in the testing room, whereas the other half were placed in a similar arena but in a separate room without task-specific cues. Analysis of the results revealed a significant interaction between the lesion and housing condition as a function of the pre-exposure. As expected, pre-exposure facilitated learning for all sham operated rats but the lesioned enriched rats performed in a paradoxical manner. These rats appeared to be confused by the pre-exposure to the testing apparatus. The findings suggest an inability of enriched lesioned subjects to distinguish between behaviourally relevant and irrelevant stimuli and are in general agreement with the findings of Kilgard and Merzenich (1998). (Approved by the Animal Care Committee, Nipissing University).

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Han JS, Bizon JL, Chun HJ, Maus CE, Gallagher M (2000) Feedback HPA axis to stress is impaired in rats with selective removal of hippocampal cholinergic input. Neuroscience 2000 Abstracts 388.16. Society for Neuroscience, New Orleans, LA.

Summary: Activation of intracellular glucocorticoid receptors (GRs) may play a permissive role in mechanisms that lead to degeneration of hippocampal neurons in pathological conditions such as Alzheimer’s disease (AD). A previous study demonstrated that loss of cholinergic input from cells in the basal forebrain, a prominent feature of AD, reduced glucocorticoid receptor mRNA expression in the hippocampus in rats (Bizon et al., 1999). This experiment was conducted to see if reduced GRs after loss of cholinergic input would impair the function of the HPA axis in response to acute restraint stress. The cholinergic lesion was made by microinjections of the immunotoxin 192-IgG-saporin into the medial septal area and the vertical limb of the diagonal band. About 2 weeks later, rats were prepared with intravenous silastic catheters in the right jugular vein. After 5 days recovery, restraint stress for 1 hr was performed at 9:00 (a.m.). Blood (∼|50ul) was sampled repeatedly via the jugular catheter immediately (0 min) and at various times following the termination of the stressor (1 hr, 2 hr, 4 hr). For each group, negative feedback after a peak response to restraint was evident as a general trend of decreasing corticosterone that approached basal values by four hours after the cessation of stress. However, the speed of recovery to baseline differed between groups. Rats with loss of cholinergic input had higher corticosterone concentrations for a longer period after restraint stress than control rats, reflecting a diminished negative feedback function. These results suggest a mechanism whereby loss of basal forebrain cholinergic neurons in AD could contribute to a dysregulation of the HPA axis and more protracted exposure to high amounts of glucocorticoids. As an extension of the glucocorticoid cascade hypothesis, glucocorticoids might then be a factor in endangering hippocampal neurons in this disease.

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Gu Z, Wortwein G, Yu J, Perez-Polo JR (2000) Model for aging in the basal forebrain cholinergic system. Antiox Redox Signal 2(3):437-447. doi: 10.1089/15230860050192215

Summary: A wide range of evidence indicates that cholinergic neurons play a role in memory and learning. Loss of these neurons is seen both in aged subjects and Alzheimer’s Disease patients. The authors discuss the use of 192-Saporin (Cat. #IT-01) to model this phenomenon. Many lesioning methods have been developed, including fimbria-fornix transections, mechanical lesions with radiofrequency or electrolysis, and intracerebral injections of excitotoxins. Information obtained through these methods suffers because non-cholinergic neurons are depleted as well as the desired cholinergic neurons. 192-Saporin provides a solution by specifically targeting and eliminating cholinergic neurons expressing p75 in the basal forebrain, closely mimicking a key component of aging.

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Gu Z, Toliver-Kinsky T, Glasgow J, Werrbach-Perez K, Perez-Polo JR (2000) NGF-mediated alteration of NF-κB binding activity after partial immunolesions to rat cholinergic basal forebrain neurons. Int J Dev Neurosci 18:455-468. doi: 10.1016/s0736-5748(00)00004-6

Summary: After injecting 1.3 µg 192-Saporin (Cat. #IT-01) into the lateral ventricle of rat brain, followed by infusion of NGF antibody, Gu et al. report changes in the activity of the transcription factor NF-B. Aged rodent brains show an increase in NF-kappaB activity. This model creates a tool to investigate decreased cholinergic function that is often associated with memory loss and cognitive deficits in the elderly and particularly in patients with Alzheimer’s disease.

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Lehmann O, Jeltsch H, Lehnardt O, Pain L, Lazarus C, Cassel JC (2000) Combined lesions of cholinergic and serotonergic neurons in the rat brain using 192 IgG-Saporin and 5,7-dihydroxytryptamine: neurochemical and behavioural characterization. Eur J Neurosci 12:67-79. doi: 10.1046/j.1460-9568.2000.00881.x

Summary: Lesioning of septohippocampal pathways has often been used as a model for Alzheimer’s disease because these lesions alter cognitive capabilities such as spatial memory. Recent work in the behavioral neurosciences has shown that other neurotransmitter systems such as GABAergic, noradrenergic, and serotonergic systems also play a role in learning and memory. Lehmann et al. combined the effects of the cholinergic immunotoxin 192-SAP (Cat. #IT-01) and the serotonergic toxin 5,7-dihydroxytryptamine to examine interactions between these two pathways. The effects of lesioning these two pathways in concert indicate that they both play roles in cognitive functions related to working memory. [192-SAP 2 µg/lateral ventricle]

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Hartlage-Ruebsamen M, Lippe WR, Schliebs R (1999) Cholinergic basal forebrain lesion results in reduced activity of neuronal NO synthase in hippocampal and neocortical areas of the rat brain. Neuroscience 1999 Abstracts 847.3. Society for Neuroscience, Miami, FL.

Summary: Nitric oxide (NO) released by cortical neurons expressing the neuronal form of NO synthase (nNOS) is known to stimulate regional cerebral blood flow and is implicated in the formation of long term potentiation in the hippocampus. Cortical nNOS containing neurons express M] muscarinic acetylcholine receptors and receive cholinergic input from the basal forebrain (BF). Consequently, it has been shown that stimulation of BF cholinergic neurons leads to increased cortical perfusion. Cholinergic cell loss in the BF, reduced cortical blood flow and memory’ dysfunction are characteristics of Alzheimer’s disease. In the present study, we investigated the impact of a selective lesion of BF cholinergic neurons by the cholinergic toxin 192IgG-saporin on the expression and substrate binding activity of nNOS in selected regions of neocortex and hippocampus in the rat. While Western blot analysis yielded no significant changes in total nNOS protein levels 7 days post lesion, nNOS catalytic and substrate binding activity was reduced in a number of hippocampal and neocortical subregions as revealed by NADPH- diaphorase enzyme histochemistry and by quantitative autoradiography using [3H]L-A,’G-nitro-arginine binding. The data suggest that cholinergic mechanisms control, at least in part, neocortical and hippocampal nNOS activity providing further evidence for an NO-mediated influence of the BF cholinergic system on memory function and cortical perfusion. Contract grant sponsor: Deutsche Forschungsgemeinschaft, SCHL 363/4-1.

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Gu Z, Toliver-Kinsky T, Glasgow J, Cain L, Perez-Polo JR (1999) NGF-mediated alteration of NF-κB binding activity after partial immuno-lesions to rat cholinergic basal forebrain neurons. Neuroscience 1999 Abstracts 300.15. Society for Neuroscience, Miami, FL.

Summary: Memory loss and cognitive deficits in die aged and in patients with Alzheimer’s disease (AD) are often associated with cholinergic deficits within the NGF-dependent cholinergic basal forebrain neurons (CBFNs) that project to the cortex, hippocampus, and olfactory bulb. Although the causes of these cholinergic deficits are not fully understood, the increases in activity of the transcription factor NF-κB in the brains from aged and AD patient may reflect chronic transcription enhancement of stress response genes that affect cholinergic expression and neuronal death. In order to ascertain whether endogenous NGF effects on ChAT and NF-κB may account for recovery from stress, a partial immunolesion (PIL) to CBFNs, which is produced by the injection of 192 IgG-saporin, an immunotoxin selectively taken up by low-affinity NGF receptor p75NTR-bearing neurons, was conducted and followed by infusion of anti-NGF. Both PIL and anti-NGF treatment decreased ChAT activity in cortex, hippocampus, and olfactory bulb. NGF protein levels increased significantly in the olfactory bulb, but not the cortex or hippocampus after PIL treatment. Infusion of anti-NGF abolished the PIL-induced NGF increases in cerebrospinal fluid. We also found that NF-κB binding activity to both the κ light chain enhancer and the ChAT promoter specific consensus sequence increased in PIL-induced cortex but not hippocampus after anti-NGF infusion as measured by electrophoretic mobility shift assays (EMSAs). This is consistent with the hypothesis that NF-κB contributes as a repressor to the transcriptional regulation of ChAT by NGF. Taken together with reports of increased levels of NF-κB activity in brains of aged rats and of AD patients, it is likely that NGF-mediated changes in NF-κB activity in part reflect responses to age-associated cholinergic deficits. (Supported in part by NINDS Grant NS 33288)

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Rossner S (1998) Cholinergic immunolesions by 192 IgG-saporin – useful tool to simulate pathogenic aspects of Alzheimer’s disease. Int J Dev Neurosci 15:835-850. doi: 10.1016/s0736-5748(97)00035-x PMID: 9568532

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