alzheimers-disease

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)

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)

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.

Related Products: ME20.4-SAP (Cat. #IT-15)

Ricceri L, Moles A, Pezzola A, Popoli P, Calamandrei G (2002) Neonatal basal forebrain cholinergic lesions disrupt retention of socially transmitted food preferences and alter EEG activity in adult rats. Neuroscience 2002 Abstracts 82.9. Society for Neuroscience, Orlando, FL.

Summary: Previous studies using selective neonatal lesions of basal forebrain cholinergic neurons showed mild long-term effects on spatial discrimination capabilities, whereas water maze learning appeared intact. In the present study we examined long-term effects of icv injections of 192 IgG saporin performed in 7-day-old rats on the social transmission of food preferences (a form of non-spatial associative memory) at adulthood. In 6-month-old rats the neonatal cholinergic lesion impaired 4-h and 24-h retention of a learned social food preference relative to controls, despite performance on an immediate retention trial was indistinguishable from controls. A second experiment excluded alterations in neophobia towards unfamiliar scented food after neonatal cholinergic lesions: level of novel food consumption did not differ between neonatally saporin-lesioned and control rats. Computerized EEG spectral analysis (FFT transform) performed in 6-month-old rats revealed that the neonatal cholinergic lesions increased δ power and reduced β power in both fronto-parietal and parieto-occipital cortex. Effectiveness of the neonatal lesion was confirmed by a marked cholinergic loss in both hippocampal and cortical regions. Altogether, behavioral and electrophysiological data suggest that the neonatal cholinergic lesion of the basal forebrain – more than the adult one – could represent a useful experimental model of Alzheimer-like memory dysfunctions.

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

Zeitschel U, Schliebs R, Rossner S, Bigl V, Eschrich K, Bigl M (2002) Changes in activity and expression of phosphofructokinase in different rat brain regions after basal forebrain cholinergic lesion. J Neurochem 83(2):371-380. doi: 10.1046/j.1471-4159.2002.01127.x

Summary: The authors used intraventricular injections of 4 µg of 192-Saporin (Cat. #IT-01) in rats to investigate whether impaired cholinergic transmission may cause metabolic changes. Although the results demonstrate an initial increase in a cortical glucose metabolic marker, this increase was transient. The authors conclude that cholinergic systems do not control cortical glucose metabolic mechanisms affected by Alzheimer’s disease.

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

Hyde LA, Crnic LS (2002) Reactivity to object and spatial novelty is normal in older Ts65Dn mice that model Down syndrome and Alzheimer’s disease. Brain Res 945:26-30. doi: 10.1016/s0006-8993(02)02500-3 PMID: 12113948

Summary: The authors hypothesized that a mouse model for Down syndrome may show some of the same cognitive deficits exhibited by rats lesioned with 192-Saporin (Cat. #IT-01), which eliminates cholinergic cells in the basal forebrain. The results suggest that in this Down syndrome model, cell loss has a much greater cognitive effect if it happens early in development as opposed to in adulthood.

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

Bitner RS, Nikkel AL (2002) Alpha-7 nicotinic receptor expression by two distinct cell types in the dorsal raphe nucleus and locus coeruleus of rat. Brain Res 938:45-54. doi: 10.1016/s0006-8993(02)02485-x

Summary: Neuronal nicotinic acetylcholine receptors (nAChRs) are suspected to play a role in neurophysiological disorders such as schizophrenia, Alzheimer’s disease, and epilepsy. Whereas the molecular and cellular properties of these receptors have been well characterized, the role of nAChRs in the nervous system is as yet unclear. The authors injected rats intracerebroventricularly with 5 µg/5 µl of anti-DBH-SAP (Cat. #IT-03) to eliminate the noradrenergic nuclei. Using these data along with data acquired by elimination of serotonergic nuclei with 5,7-DHT, the authors showed that both noradrenergic nuclei in the locus coeruleus and serotonergic nuclei in the dorsal raphe nucleus express the alpha-7 nAChR subunit.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Butt AE, Noble MM, Rogers JL, Rea TE (2002) Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis. Behav Neurosci 116(2):241-255. doi: 10.1037//0735-7044.116.2.241

Summary: 192-Saporin (Cat. #IT-01) administration to the basal forebrain has frequently been used in rats to create a model for Alzheimer’s disease. The authors used 0.2 µl bilateral injections of 0.4 µg/µl 192-SAP into the nucleus basalis magnocellularis (NBM). Previous studies using non-specific excitotoxic agents have suggested the involvement of the NBM in learning and memory. The authors confirm more recent findings that indicate some of the deficits produced by these excitotoxins are due to the non-specific lesioning caused by these agents. The highly selective cholinergic lesioning produced by 192-Saporin left simple association learning intact but impaired more complicated configural association processes.

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

Himmelheber AM, Sarter M, Bruno JP (2001) The effects of manipulations of attentional demand on cortical acetylcholine release. Brain Res Cogn Brain Res 12(3):353-370. doi: 10.1016/s0926-6410(01)00064-7

Summary: Cortical cholinergic afferents from the basal forebrain are suspected to be involved in attentional tasks. Regulatory impairment of these afferents has been hypothesized to contribute to attentional deficits seen in conditions as diverse as Alzheimer’s disease and schizophrenia. The authors have previously shown that 192-Saporin (Cat. #IT-01) lesions result in severe impairments in tasks requiring sustained attentional processing. In these experiments the authors suggest that cell response is dependent on the level of demand. They demonstrate that removal of p75+ cells (0.5 µg/µl bilaterally infused into the nucleus basalis region in rat) impairs sustained attentional performance, but does not impact low-demand task performance.

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