alzheimers-disease

Bailey AM, Rudisill ML, Hoof EJ, Loving ML (2003) 192 IgG-saporin lesions to the nucleus basalis magnocellularis (nBM) disrupt acquisition of learning set formation. Brain Res 969(1-2):147-159. doi: 10.1016/s0006-8993(03)02294-7

Summary: Previous studies by Bailey and others have used quisqualic acid to lesion the nucleus basalis (nBM) in order to understand Alzheimer’s disease. Injections of 75 ng of 192-Saporin (Cat. #IT-01) were made into each of four sites in the rat nBM. Behavioral tests showed initial learning set deficits followed by recovery, whereas with quisqualic acid lesions, the deficits were profound. The authors conclude noncholinergic neurons are involved in learning set formation.

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

Hartonian I, Mufson EJ, de Lacalle S (2002) Long-term plastic changes in galanin innervation in the rat basal forebrain. Neuroscience 115(3):787-795. doi: 10.1016/s0306-4522(02)00453-0

Summary: One hallmark of Alzheimer’s disease is the hyperinnervation of surviving cholinergic basal forebrain neurons with galanin-IR fibers. This may exacerbate the cholinergic deficit. The authors injected 192-Saporin (140 nl of 0.075 mg/ml, Cat. #IT-01) into the diagonal band of Broca of rats. An increase in galanin immunoreactivity was observed as early as 1 hour post-injection, and persisted as long as 6 months.

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

Harrell LE, Parsons DS, Conger K, Kolasa K (2002) ß1 adrenergic antagonist effect on brain muscarinic cholinergic receptors. Neuroscience 2002 Abstracts 685.13. Society for Neuroscience, Orlando, FL.

Summary: Degeneration of basal forebrain cholinergic system and sympathetic ingrowth appear to be pathologic changes in Alzheimer’s Disease (AD). An imbalance between these systems may mediate cognitive deficit in AD. To model this situation, 192-IgG-Saporin, a specific cholinergic immunotoxin, was infused intraventricularly to induce cholinergic denervation and sympathetic ingrowth into cortex and hippocampus. After 8 weeks of intraperitoneal injection of Metoprolol, β1 antagonist, at 2.5 mg/kg and 5 mg/kg, the Kd and Bmax of dorsal hippocampus (DH), anterior (AC) and entorhinal (EC) cortex was determined via [3H]-QNB, muscarinic antagonist, binding. Low dose Metoprolol increased Kd in the sympathetic ingrowth, cholinergic denervation, ganglionectomized groups compared to control and vehicle groups (p<.05). Affinity of AC=DH but was > than EC (p<.02). Bmax was greater in AC than DH (p<.05) > than EC (p<.02). Controls and ganglionectomized had > Bmax in AC and EC (p<.03). EC had > Bmax in control and ganglionectomized animals (p<.04). High dose Metoprolol induced a greater affinity in DH>AC>EC (p<.05). No effect was found on Bmax.The results of our study suggest that a β1 antagonist, which is used clinically, can alter the number and affinity of cholinergic receptors, which in turn could potentially alter the AD patients' response to cholinergic therapy.

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

Sheehan JJ, Tsirka SE (2002) Reduction of microglia cell populations before induction of excitotoxicity reduces neurodegeneration. Neuroscience 2002 Abstracts 606.9. Society for Neuroscience, Orlando, FL.

Summary: Excitotoxicity is thought to be a component of many neurodegenerative diseases including Alzheimer’s and stroke. In excitotoxicity, as well as other injury models, microglia have been found to have both neuroprotective and neurodegenerative roles. To lend further insight into this controversy we utilized an immunotoxin selective for monocyte derived cell populations including microglia. The immunotoxin will selectively kill microglia and is not toxic to neurons or other glia populations in culture. In addition, infusion of the immunotoxin into the hippocampus of C57/Bl mice results in a selective reduction in endogenous microglial cell populations in this region. Furthermore, this reduction occurs without any perturbation of other cell types or the extracellular matrix. If depletion of microglia in this manner precedes excitotoxic injury, then hippocampal neurodegeneration is significantly reduced. These results agree with other work in our lab, which suggests that microglial cells exhibit neurotoxic properties in excitotoxicity.

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)

Herron P, Ismail NS (2002) Effects of cholinergic depletion on the expression of synaptic proteins and functional properties in the rat somatosensory cortex. Neuroscience 2002 Abstracts 256.1. Society for Neuroscience, Orlando, FL.

Summary: Loss of acetylcholine (ACh) has been shown to contribute to numerous cognitive, perceptual, and behavioral deficits in animal studies and in Parkinson and Alzheimer’s patients. The purposes of these experiments were to determine the effects of cholinergic depletion on the expression of glutamic acid decarboxylase (GAD), N-methyl-D-aspartate (NMDA) receptors, synaptophysin, and CaMKII and on functional properties of single neurons in the somatosensory cortex. These experiments were done in the posteromedial barrel subfield (PMBSF) cortex of young adult Sprague-Dawley rats. Selective lesion of cholinergic neurons in the NBM was achieved with intraventricular injections of the immunotoxin (IT), 192 IgG saporin. Electrophysiological recordings and Western blot analyses for the expressions of GAD, NMDA receptors, and synaptophysin were done after a two-week post-injection survival period. The magnitude of evoked and spontaneous activities and the receptive field size of single neurons in the somatosensory cortex were investigated. Recordings and Western blot analyses were obtained from the same area of the PMBSF cortex. Results show that cholinergic depletion causes a significant decrease (11.7%) in the magnitude of evoked activity and an increase (10.7%) in the size of receptive fields. GAD, NMDA receptors, and synaptophysin levels in the in the PMBSF cortex were reduced 25%, 12%, 29%, and 12.5% respectively, in cholinergic depleted animals. Thus, cholinergic depletion leads to effects that significantly alter the expression of synaptic proteins involved in plasticity, learning, and memory.

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

Kolasa K, Harrell LE (2002) Apoptotic affect of cholinergic denervation and hippocampal sympathetic ingrowth following selective immunolesioning with 192-IgG-saporin in rat hippocampus. Neuroscience 2002 Abstracts 295.16. Society for Neuroscience, Orlando, FL.

Summary: In rat, injection of specific cholinotoxin, 192IgG-saporin, into the medial septum (MS) results not only in a selective denervation of hippocampus(CD), but in an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion, into the hippocampus(HSI). A similar process, in which sympathetic axons invade hippocampus, may also occur in Alzheimer’s disease(AD). Our previous studies using MS electrolytic lesions suggested that HSI and CD appear to induce opposite effect on apoptotic markers. Apoptosis has also been implicated in some aspects of AD. By using 192IgG-saporin we have been able to more specifically and precisely study the affect of apoptosis on HSI and CD. Thus, 12 weeks after injection we measured apoptotic protein expression and DNA degradation using Western blot and in situ techniques e.x. TdT-mediated dUTP nick end labeling(TUNEL). Choline acetyltransferase activity (ChAT) and norepinephrine (NE) level was also detected. Like the previous results, we have found increase in apoptotic markers in CD group, while HSI reduced or normalized apoptotic effect to the control group level. We also found decrease in ChAT activity in HSI and CD groups of dorsal hippocampus.The results of the study suggest that cholinergic denervation is responsible for most of the proapoptotic responses, while hippocampal sympathetic ingrowth produced protective effect in the process of programmed cell death in rat dorsal hippocampus.

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

Helm KA, Ziegler DR, Gallagher M (2002) Habituation and dexamethasone (DEX) suppression of the stress response following selective lesions of cholinergic input to hippocampus in rats. Neuroscience 2002 Abstracts 370.1. Society for Neuroscience, Orlando, FL.

Summary: Hippocampal neurons have been identified as targets for glucocorticoids that exert inhibitory control over hypothalamic-pituitary-adrenocortical (HPA) axis activity. Prior research has shown that selective removal of cholinergic input to the hippocampus reduces mRNA expression for low-affinity glucocorticoid receptors, while leaving unaffected both mineralocorticoid receptor mRNA and basal levels of circulating corticosterone (CORT). The current study investigated the possibility that loss of cholinergic support from cells in the basal forebrain alters the CORT response to stress. Cholinergic lesions were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band, and 3 weeks later rats were subjected to six daily sessions of 30 min restraint stress. Blood samples taken before, during and after stress on Day 1 revealed a prolonged elevation of CORT in response to acute stress in cholinergic lesioned rats. After 5 days of chronic stress, however, both groups significantly habituated to the stressor, as indicated by similarly low CORT profiles throughout both the response and recovery period. Against this similar background, rats were administered a Dexamethasone (DEX) challenge on Day 6, and DEX-induced suppression of endogenous CORT before, during and after stress was attenuated in lesioned rats. These results indicate a mechanism whereby loss of cholinergic function (e.g. in aging and Alzheimer’s Dementia) may compromise the dynamic range of sensitivity to glucocorticoid mediated stress pathways in the brain.

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

Bradley QR, Borowski TB, de Lacalle S (2002) The effects of 17ß-estradiol on odor discrimination of ovariectomized and intact young and aged rats following unilateral lesions of the nucleus of the horizontal diagonal band of broca (HDB). Neuroscience 2002 Abstracts 385.3. Society for Neuroscience, Orlando, FL.

Summary: Estradiol exerts beneficial effects on cognitive performance. The present study was designed to investigate the effect of estradiol on learning and memory following the destruction of cholinergic neurons of the HDB, a basal forebrain region that exhibits significant neuronal loss during aging and may underlie the cognitive deficits associated with Alzheimers disease. Young (3 months old) and aged (20 months old) ovariectomized and gonadally intact Fisher 344 female rats were given unilateral lesions of the HDB with the cholinergic immunotoxin 192 IgG-saporin (.075mg/ml). Starting one week after surgery rats were tested on an odor discrimination task whereby rats were trained to associate a food reward buried within a scented cup of sand relative to a dissimilar scented cup of sand that contained no reward. Following stable levels of acquisition and retention, subjects were exposed to a reversal procedure where the previously unrewarded cup was now baited. Odor discrimination acquisition, retention and reversal were assessed before and after one month of 17β-estradiol exposure or placebo. Analysis of learning curves revealed that young rats performed better than the aged animals independent of estradiol treatment during the reversal component of the task. However, within each age group 17β-estradiol treatment facilitated performance in ovariectomized rats relative to placebo controls. These findings shed new light on the cognitive enhancing properties of estradiol in age-related cholinergic neurodegenerative disorders.

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

Sugaya K, Qu T (2002) Stem cell transplantation strategies for a lesion model of Alzheimer’s disease. Neuroscience 2002 Abstracts 237.1. Society for Neuroscience, Orlando, FL.

Summary: Stem cell transplantation strategies are advocated in Alzheimer’s disease (AD) neuroregeneration therapy. Since basal cholinergic neurons, which selectively degenerate in AD, extend long projections into the cortex and hippocampus, a stumbling block for neuroreplacement treatment in AD is whether these degenerating cholinergic cells can be replaced by the transplantation of stem cells. To answer this question, we transplanted human neural stem cells (HNSCs) into nucleus basalis magnocelluerlis (NBM) lesion model rats. The lesion was induced either by an injection of ibotenic acid or by anti-NGF receptor antibody conjugated with saporin. HNSCs were labeled by the incorporation of bromodeoxy uridine (BrdU) into the nuclei and simultaneously injected into the contralateral side of the lateral ventricle (Qu, 2001) of the NBM lesioned animal. Four weeks after the surgery, the brain was examined by immunohistochemistry for choline acetyl transferase (ChAT), βIII-tubulin, glial fibrillary acidic protein (GFAP), and BrdU. We detected many GFAP-positive cells in the lesion area, but they were not BrdU-positive, indicating astrocytes activation in this area. We found BrdU-positive cells with ChAT or βIII-tubulin immunoreactivity in the lesion site, indicating that HNSCs migrated to the lesion site and had differentiated into cholinergic and other neuronal cells. These neuronally differentiating HNSCs were rather morphologically premature neurons, and although we have yet to confirm the physiological function or any projections into the hippocampus or cortex, our results could indicate that we have pioneered a positive study of neuroreplacement treatment for cholinergic neurons in AD.

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

Varga C, Grosche J, Brauer K, Seeger J, Harkany T, Hartig W (2002) Cholinergic neurons in the rabbit forebrain: Chemoarchitecture, in vivo labeling, immunolesions. Neuroscience 2002 Abstracts 35.3. Society for Neuroscience, Orlando, FL.

Summary: While the rabbit basal forebrain and its cholinergic components became useful targets for modeling of neuropathological changes associated with Alzheimer’s disease, their neuroanatomical organization is still largely elusive. Hence, we focused on (i) the number of cholinergic basal forebrain neurons (CBFN)in the major nuclei based on choline acetyltransferase (ChAT) immunoperoxidase labeling, (ii) the density of ChAT-immunoreactive fibers in distinct neocortical and hippocampal areas, (iii) mapping of projecting CBFN by low-affinity neurotrophin receptor p75 (p75NTR ) staining and (iv) the double fluorescence labeling of ChAT and the neuronal markers p75NTR, nitric oxide synthase (NOS), calbindin, calretinin, parvalbumin, tyrosine hydroxylase and substance P. While cholinergic interneurons were found in the hippocampus, they were not detectable in the neocortex. CBFN were shown to abundantly co-express p75NTR, except in the substantia innominata and ventral pallidum. Whereas cholinergic neurons were devoid of most investigated markers, a subset also contained calbindin or NOS. The selective in vivo labeling of CBFN was achieved with intracerebroventricularly (i.c.v.) injected carbocyanine 3-conjugated ME20.4IgG that recognizes an extracellular epitope of p75NTR. Parallel experiments revealed that the i.c.v. injection of ME20.4IgG-saporin conjugates led to the specific immunolesion of cholinergic cells in about one week, whereas long-term effects of the immunotoxin remain to be further elucidated.

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