alzheimers-disease

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.

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

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.

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

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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McDonald MP, Overmier JB (1998) Present imperfect: a critical review of animal models of the mnemonic impairments in Alzheimer’s disease. Neurosci Biobehav Rev 22(1):99-120. doi: 10.1016/s0149-7634(97)00024-9 PMID: 9491942

Giulian D, Haverkamp LJ, Yu JH, Karshin W, Tom D, Li J, Kirkpatrick J, Kuo YM, Roher AE (1996) Specific domains of ß-amyloid from Alzheimer plaque elicit neuron killing in human microglia. J Neurosci 16:6021-6037. doi: 10.1523/JNEUROSCI.16-19-06021.1996 PMID: 8815885

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Wiley RG, Berbos T, Deckwerth T, Johnson EM, Lappi DA (1995) 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. doi: 10.1016/0022-510x(94)00226-e PMID: 7738592

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

Okamura H, Kitahamara K, Mons N, Matsumoto Y, Ibata Y, Geffard M (1991) Heterogeneous distribution of L-DOPA immunoreactivity in dopaminergic neurons of the rat midbrain. (eds. Nagatsu T, Fisher A, Yoshida M). In: Basic, clinical, an therapeutic aspects of Alzheimer’s and Parkinson’s diseases 423-426. Plenum Press, NewYork and London. doi: 10.1007/978-1-4684-5844-2_87

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