alzheimers-disease

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)

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)

Lee KY, Leos R, Borowski TB, de Lacalle S (2001) Bcl-2 improves survival of lesioned cholinergic neurons. Neuroscience 2001 Abstracts 803.6. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease is associated with the progressive cell death of cholinergic neurons in the central nervous system (CNS). A current challenge is to develop therapeutic approaches that could prevent atrophy and loss of CNS neurons, and promote regeneration of their processes. The purpose of our study is to determine the therapeutic potential of the antiapoptotic gene B-cell lymphoma 2 (bcl-2) on the cholinergic system of the basal forebrain (BF). Retrograde degeneration in the BF of 3-month-old rats was induced by unilateral injection of the immunotoxin 192 IgG-saporin into the entorhinal cortex. Fifteen minutes later, an injection of 5 µg of the pa22bgala4bcl-2 plasmid was placed into the BF. Similar procedures were followed for BF injections of a control plasmid or vehicle alone. We found that a single injection of bcl-2 plasmid into the BF of the lesioned side increased survival of cholinergic neurons ~50%, as compared to vehicle controls. In addition, cell survival was close to 100% of intact side with bcl-2 injections, compared to a 50% cell loss in animals injected with a control DNA. Our results indicate that an injection of the bcl-2 gene into the BF prevents loss of cholinergic neurons that have been injured by IgG-saporin. Mechanisms by which bcl-2 may protect cholinergic neurons could include retrograde transport of the plasmid to the nucleus and subsequent neuroprotective effects of increased levels of bcl-2 protein. Our results, in conjunction with other studies, suggest that neurodegeneration might be amenable to gene therapy.

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

Harrell LE, Kolasa K, Parsons DS, Conger K (2001) α-1 adrenergic agonist effect on cholinergic muscarinic receptors. Neuroscience 2001 Abstracts 549.16. Society for Neuroscience, San Diego, CA.

Summary: Degeneration of the basal forebrain cholinergic system and sympathetic ingrowth appear to be pathological changes in Alzheimer’s Disease patients (AD), leading to an alteration in the balance between both systems and may mediate cognitive deficits in AD. In an attempt to model this situation, intraventricular injection (ivc) of a specific cholinergic immunotoxin, 192-IgG-saporin, has been used to induce peripheral noradrenergic fibers to grow into cortex and hippocampus after cholinergic denervation of rat cortex (CCD) and hippocampus (HCD). This adrenergic reorganization has been termed cortical (CSI) and hippocampal (HSI) sympathetic ingrowth. 192-IgG-saporin ivc injection was followed by intraperitoneal (ip) treatment with α1 agonist methoxamine. Thus the effects on choline acetyltransferase (ChAT) activity, norepinephrine (NE) level and muscarinic acetylcholine receptors (mAChR) were studied in rat hippocampal and cortical brain tissue. We found that 192-IgG-saporin produced significant decrease in ChAT activity in all experimental groups and areas. Methoxamine (3 and 6 mg/kg ip) did not affect NE levels. It produced significant decrease in mAChR affinity in the cholinergic denervation group and no significant increase in mAChR density in cholinergically denervation groups of dorsal hippocampal and cortical areass. Results of the present study indicate the influence of α1 agonist treatment on mAChR and may provide new concepts for the future combination drug therapy for AD patients.

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

Kolasa K, Harrell LE, Parsons DS, Conger K (2001) α-1 adrenergic antagonist effect on cholinergic muscarinic receptors. Neuroscience 2001 Abstracts 549.17. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic denervation of cortex and hippocampus in rat causes an unusual neuronal rearrangement, in which peripheral sympathetic fibers, originating from superior cervical ganglia, grow into the cholinergically denervated areas. This process has been termed cortical (CSI) and hippocampal sympathetic ingrowth (HSI). A similar process may occur in Alzheimer’s Disease (AD). Recent studies suggest that the balance between central adrenergic and cholinergic systems may be important for normal learning and memory, while the alterations of these systems may play a critical role in cognitive deficits of AD. To better understand this situation specific cholinotoxin, 192-IgG-saporin, was intraventricularly (ivc) injected to produce a selective loss of cholinergic cells in rat basal forebrain nuclei, cholinergically denervating hippocampal (HCD) and cortical areas (CCD). This effect was confirmed by significant decrease in choline acetyltransferase activity in all groups and brain structures.192-IgG-saporin injection was followed by a treatment with α1-adrenergic antagonist prazosin to determine the effect on hippocampal and cortical muscarinic acetylcholine receptors (mAChR) and norepinephrine (NE) level. Prazosin (0.5 & 2 mg/kg ip) produced decreases in NE levels of HSI and CSI and induced no significant increase in mAChR affinity in HSI and CSI groups in dorsal hippocampus,anterior and entorhinal cortex. Injected at the dose of 2 mg/kg it increased mAChR density in CSI of both cortical areas. The present results began to define the interaction between adrenergic and cholinergic systems, as α1 antagonist treatment affects mAChR,a potential therapeutic target in AD.

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

Hartonian I, de Lacalle S (2001) Long-term plastic changes in galanin innervation in rat basal forebrain. Neuroscience 2001 Abstracts 254.1. Society for Neuroscience, San Diego, CA.

Summary: Galanin (GAL) immunoreactive (-ir) fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer’s Disease (AD), perhaps exacerbating the cholinergic deficit. The purpose of our study is to determine whether a similar hyperinnervation of GAL-ir fibers occurs following intraparenchymal injection of 192-IgG saporin, a specific cholinergic neurotoxin, within the horizontal diagonal band of Broca (HDB), in 3-month-old rats, and to identify its origin. Immunotoxic lesions produced on average a 31% reduction in cholinergic cell counts on the lesioned side versus the spared side. Hyperinnervation of GAL-ir fibers was observed within and adjacent to the HDB in 28 out of 36 rats, and this effect persisted across time, with 6 months being the longest time examined. Morphometry revealed an increase in the number of GAL-ir cells on the lesioned basal forebrain, as compared to control. A similar change could not be detected in the number of GAL-ir neurons in the amygdala or the bed nucleus of the stria terminalis. Although there was no significant correlation in the amount of cell loss and of GAL hyperinnervation, we suggest that GAL hyperinnervation is triggered by the loss of cells because it is persistent across time. Our data suggests that this hyperinnervation is the result of overexpression of GAL in some cholinergic neurons of the basal forebrain. Since GAL is known to inhibit acetylcholine release, exacerbating the cholinergic dysfunction in AD, this model can be useful to test the efficacy of GAL inhibitors.

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