alzheimers-disease

Kar S, Hawkes C, Jhamandas JH (2004) Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin induces activation of glycogen synthase kinase-3β activity. Neuroscience 2004 Abstracts 92.2. Society for Neuroscience, San Diego, CA.

Summary: Glycogen synthase kinase-3β (GSK-3β) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is negatively regulated by phosphorylation of Ser9 and upregulated by Tyr216 phosphorylation. Activation of GSK-3β induces apoptosis in a variety of cultured neurons and the inhibitory control of its activity by Akt kinase is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192-IgG saporin was used to address the potential role of GSK-3β in the degeneration of the basal forebrain cholinergic neurons which are preferentially vulnerable in Alzheimer’s disease (AD) brain. Our results show that GSK-3β colocalizes with a subset of the forebrain cholinergic neurons and that loss of these neurons is accompanied by a transient decrease in phospho-Akt and phospho-Ser9 GSK-3β levels in the basal forebrain, hippocampus and the cortex. Neither total Akt, GSK-3β, nor phospho-Tyr216 GSK-3β levels were significantly altered in the aforesaid brain regions of treated animals. These results provide the very first evidence that increased GSK-3β activity is associated with in vivo degeneration of the forebrain cholinergic neurons and thus may be involved in the loss of these neurons as observed in AD brains.

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Kolasa K, Parsons D, Conger K, Harrell LE (2004) Neurotrophic modulation of cholinergic denervation and hippocampal sympathetic ingrowth following immunolesioning with 192 IgG-saporin. Neuroscience 2004 Abstracts 92.9. Society for Neuroscience, San Diego, CA.

Summary: Injection of specific cholinotoxin, 192 IgG-saporin into the medial septum (MS)of rat induces not only a selective cholinergic denervation of hippocampus (CD),but an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion,into the hippocampus (HSI).A similar process,in which sympathetic noradrenergic axons invade hippocampus,may also occur in Alzheimer’s disease(AD). The severity of cognitive decline in AD patients has been linked to multiple factors including cholinergic and neurotrophic factors and their receptors, which undergo selective alterations throughout the progression of AD.It is known that the sites of neurotrophin synthesis in the septo-hippocampal system are predominantly hippocampal neurons. By using 192 IgG-saporin we have been able to mimic some of the cardinal features of AD e.x.cholinergic denervation and hippocampal sympathetic ingrowth and study their effect on growth factors in dorsal hippocampus. Thus,12 weeks after injection of 192 IgG-saporin we measured neurotrophic protein and mRNA expression using Western blot and RT-PCR techniques,respectively. Choline acetyltransferase activity(ChAT)and norepinephrine(NE) concentration was also detected.There was no change in NGF,BDNF,NT3,GDNF mRNA expression,but we have found significant decrease in 240 bp and increase in 328 bp of persephin mRNA expression in CD, and “normalization” in HSI group. No significant alteration was found in NGF and persephin protein expression, but significant decrease in mature form of BDNF protein expression was found in CD, with “normalization”in HSI group.Results of the study suggest that growth factors are affected by cholinergic denervation and may play an important role in regulation and development of HSI,which might be a beneficial phenomenon for restoration of at least some cognitive function.

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Ricceri L, Minghetti L, Moles A, Popoli P, Confaloni A, De Simone R, Piscopo P, Scattoni ML, di Luca M, Calamandrei G (2004) Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats. Exp Neurol 189(1):162-172. doi: 10.1016/j.expneurol.2004.05.025

Summary: A distinctive feature of Alzheimer’s disease is the loss of cholinergic neurons in the basal forebrain (BF). The authors investigated long-term effects of BF cholinergic lesions on several parameters. Administration of 0.21 µg of 192-Saporin (Cat. #IT-01) to the third ventricle of 7 day-old rats was followed by an evaluation of protein levels and cortical EEG patterns at 6 months of age. The findings indicate that permanent neonatal BF cholinergic damage may provide a model for abnormal adult cholinergic function.

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Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004) Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305-3316. doi: 10.1111/j.0953-816X.2004.03439.x

Summary: In Alzheimer’s disease basal cholinergic degeneration is accompanied by glial activation and the release of pro-inflammatory cytokines. To investigate whether neural events other than degeneration can cause effects of Alzheimer’s disease, the authors treated mice with minocycline after lesioning the basal forebrain with 3.6 µg of mu p75-SAP (Cat. #IT-16). Administration of minocycline reduced the loss of cholinergic neurons, reduced glial response to the lesion, and lessened the cognitive impairment due to mu p75-SAP lesions.

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Kolasa K, Harrell LE (2003) Combined lesions of central cholinergic and noradrenergic denervation in the rat using 192 IgG-saporin and DSP-4 as an animal model of Alzheimer’s disease. Neuroscience 2003 Abstracts 842.6. Society for Neuroscience, New Orleans, LA.

Summary: To better model the consequences of persistent cholinergic hypofunction observed in Alzheimer’s disease, medial septum (MS) lesions were made by using specific cholinotoxin 192-IgG saporin. In this study the effect of simultaneous hippocampal cholinergic denervation, induced by intraseptal injection of 192-IgG saporin, and central noradrenergic denervation, induced by systemic injection of DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) was examined in the rat dorsal hippocampus. DSP-4, an adrenergic neurotoxin selective for locus coeruleus innervated brain regions, induced a decrease in norepinephrine (NE) concentration in hippocampus. MS lesions resulted not only in selective cholinergic denervation of hippocampus (CD; superior cervical ganglion removed to prevent ingrowth of peripheral NE fibers), but also ingrowth of NE fibers into the hippocampus (HI; superior cervical ganglion left intact). MS lesions also resulted in a significant loss of choline-acetyltransferase activity in HI and CD groups, and an increase in NE in the HI group. In the HI group, but not in CD or control groups, visualization of hippocampus revealed a dense NE innervation with fine NE fibers with varicosities. Combination of MS lesion and DSP-4 treatment resulted in a reduction of NE concentration in HI group, with concomitant decrease in visualization of NE fibers. Those that remained were thick with sparse varicosities, possibly derived from peripheral sympathetic ingrowth. Elevated NE concentration and NE fiber number following specific cholinergic lesions might reflect compensatory sprouting of both central and peripheral adrenergic fibers into the hippocampus. Thus, noradrenergic sprouting in response to cholinergic denervation of hippocampus might be a valuable model for studying mechanisms as well as the consequences of neuronal plasticity in the mature CNS.

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Dudkin KN, Chueva IV, Makarov FN, Beach TG, Roher AE (2003) Impairments of working memory processes on a model of Alzheimer’s disease in monkeys. Neuroscience 2003 Abstracts 626.8. Society for Neuroscience, New Orleans, LA.

Summary: We have investigated the characteristics of visual working memory in a delayed-discrimination task in a model of Alzheimer’s disease (AD) in rhesus monkeys. Three animals received unilateral stereotaxic intracerebroventricular injection of the nucleus basalis of Meynert and three monkeys received sterile saline injections and thus served as controls. The lesioning agent consisted of a ribosomal toxin, saporin, conjugated to monoclonal antibodies against (the nbM lesion) the p75 neurotrophin receptor (p75NTR), which is expressed almost exclusively on cholinergic neurons of the nbM. The rationale for the model is the same as for a rabbit model of AD (Roher et al, Ann. NY Acad Sci. 2000). The monkeys were trained to discriminate stimuli with different types of visual information (spatial frequency gratings, color, spatial choice, spatial relationships between components of objects). The data obtained demonstrate that the nbM lesioning agent had a weak effect on visual differentiation without delay (long-term memory), but significantly decreased the duration of information storage (by a factor of 2 – 3) in working memory later two months after injection. These changes depended on temporal stage after injection and stimulus properties, and were accompanied by increase of motor reaction time and of refusal of task decision. In monkeys that were sham injected, there were no alterations in working memory characteristics. The results suggest that considerable worsening of the working memory characteristics for monkeys after lesion of the nbM reflects the formation of an AD model in these monkeys. The principles of functional organization of working memory and role of pathology of the cortical mechanisms in an impairment of memory characteristics are discussed.

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

Janssen WG, Andrews G, Tomey MI, Baxter MG, Morrison JH (2003) Combined bilateral perforant path lesions with lesions of the cholinergic system: an ultrastructural immunogold analysis of nmdar1 representation within the dentate gyrus. Neuroscience 2003 Abstracts 676.26. Society for Neuroscience, New Orleans, LA.

Summary: Alzheimer’s disease is characterized by deterioration of cholinergic input to the hippocampus, as well as degeneration of input from the entorhinal cortex to the dentate gyrus(DG). Studies have demonstrated an upregulation of the NMDA receptor subunit, NR1, following unilateral ablatement of the perforant path(pp). We hypothesized that cholinergic innervation might be essential for DG plasticity following pp ablation. Our study was designed to investigate the synaptic distribution of NR1 following combined 192 IgG-Saporin lesions of the medial septum/vertical diagonal band(MS/VDB) and bilateral(bilat) pp knife cut ablation. Animals received bilat-pp lesions 2-3 weeks days post MS/VDB and were sacrificed 17 days following pp lesion. Four groups of rats were tested: 1)MS-VDB with sham bilat-pp; 2)sham MS-VDB with bilat-pp; 3)MS-VDB with bilat-pp; 4)sham MS-VDB with sham bilat-pp. Using postembedding immunogold electron microscopy and SynBin, a program designed for quantification and compartmentalization of immunogold particles at the synaptic level, we investigated these effects in the outer molecular layer of the DG in a pilot study with 2 animals/group. Initial results suggest that the synaptic pools of NR1 within post-synaptic compartments were not affected with single MS/VDB, but that a long term synaptic down regulation of NR1 follows bilat pp lesion that is not affected by the additional removal of cholinergic input. While these combined lesions do not alter the pattern of synaptic NR1 receptor distribution following pp lesions, these data has important implications for lesion-induced hippocampal plasticity as well as structural and functional recovery.

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Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AE (2003) Neuroinflammatory response to mu p75-saporin immunotoxin-induced degeneration of basal forebrain cholinergic neurons. Neuroscience 2003 Abstracts 527.15. Society for Neuroscience, New Orleans, LA.

Summary: Basal forebrain cholinergic neurons, which provide the major cholinergic innervation to the cortical regions and play a key role in the processing of information involved in cognitive processes, degenerate during both normal aging and Alzheimer’s disease. Neuroinflammation, specifically the activation of microglia, is known to affect the progression of neuronal degeneration. Activated microglia produce inflammatory mediators that have neuropathic as well as neuroprotective actions, and it has been suggested that inflammatory mediators produced by activated microglia may play a role in the decline of specific neuronal sub-types in neurodegenerative diseases. The immunotoxin mu p75-SAP has been shown to selectively destroy cholinergic neurons in the basal forebrain of mice, resulting in reduced choline acetyl-transferase activity and cognitive impairments. To characterize the inflammatory response to mu p75-SAP lesions, 3 month-old mice received icv injections of mu p75-SAP (3.6 mg) followed by treatment with an anti-inflammatory agent, minocycline (45 mg/kg i.p.), or saline. Seven days after lesioning, immunohistochemistry was used to analyze markers for cholinergic and non-cholinergic neurons and inflammation. Cholinergic lesioning resulted in a dramatic increase in CD45, a microglial marker, but no change in GFAP, an astroglial marker, in the basal forebrain region. Lesioned animals had elevated levels of phosphorylated p38, a MAP kinase protein involved in inflammatory pathways. Minocycline treatment reduced this inflammatory response. Furthermore, preliminary results suggest that animals treated with minocycline after mu p75-SAP lesioning are partially protected from cholinergic degeneration.

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Muir JL, Harrison FE (2003) H3 receptor antagonists modulate behaviour in a visual spatial attention task in rats with selective lesions of the nucleus basalis magnocellularis. Neuroscience 2003 Abstracts 296.7. Society for Neuroscience, New Orleans, LA.

Summary: It is well known that the cholinergic system suffers a large amount of damage in Alzheimer’s Disease (AD). The histaminergic system is known to interact with the cholinergic system but is thought to be largely spared in AD. Compounds which affect histaminergic transmission therefore offer a new further therapeutic avenue to be considered. The effects of two selective H3 receptor antagonists, Thioperamide (1.0, 3.0, 10.0mg/kg) and Ciproxifan (1.5, 3.0, 5.0mg/kg), were investigated for their ability to modulate visual spatial attention using the Five Choice Serial Reaction Time Task. The animal model used was that of cholinergic lesions of the nucleus basalis Magnocellularis (nbM) in the basal forebrain using the selective immunotoxin IgG Saporin. Thioperamide, without affecting overall accuracy, showed very strong trends towards a reduction in anticipatory responses in both sham and lesion groups and also showed a slight reduction in perseverative responses. The more potent Ciproxifan showed no overall change in accuracy but led to a reduction in the anticipatory responses in nbM lesioned animals at all three doses of the drug, returning them to equivalent levels of responses to the sham group. This effect was independent of any overall decrease in activity levels as there were no concomitant changes in response latencies or number of trials completed. Hence these pharmacological manipulations reduced the levels of impulse behaviours manifest by lesioned animals.

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Tomaszewicz M, Rossner S, Schliebs R, Cwikowska J, Szutowicz A (2003) Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin. J Neurochem 87(2):318-324. doi: 10.1046/j.1471-4159.2003.01983.x

Objective: To investigate whether cortical cholinergic input affects acetyl-CoA metabolism in cholinoceptive cortical target regions.

Summary: Alzheimer’s disease subjects often show deficits in cerebral glucose metabolism. The data show evidence of differential distribution of acetyl-CoA in subcellular compartments of cholinergic and non-cholinergic nerve terminals.

Usage: Rats received 4 µg 192-IgG-SAP (Cat. #IT-01) into the left lateral ventricle.

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