alzheimers-disease

Clausen B, Klipec W, Bastlund J, Collins M (2011) P300-like event related potentials in IgG192-saporin induced rat model of Alzheimer´s disease. Neuroscience 2011 Abstracts 550.01. Society for Neuroscience, Washington, DC.

Summary: The P300 event-related potential (ERP) is a time-locked response to rare, response-relevant stimuli. Decreased ERP amplitude is correlated with decreased memory function. Not surprisingly, alterations in P300 ERP amplitude are commonly associated with the progressive disruption of cognitive function in human Alzheimer’s disease. Here, a rat model of Alzheimer’s disease was created by injecting the antibody-linked toxin, IgG192-saporin, into the basal forebrain, producing a progressive degeneration of cholinergic cells to mimic the cholinergic degeneration that is part of Alzheimer’s disease. The goal of this experiment was to investigate the rat model by examining the relationship between the expected degenerative deficits and possible changes in the EEG patterns. Following preliminary training that has produced reliable P300-like ERPs in prior experiments in our lab, half of the rats were injected with IgG192-saporin (lesioned), while the other half were injected with saline (controls). Recording electrodes were surgically implanted on the surface of the brain and in the prefrontal cortex (PFC) and ventral hippocampus (vHipp). Following recovery, P300-like ERP data was recorded for three weeks, after which a ChAT analysis of choline acetyltransferase activity confirmed the extent of cholinergic damage in PFC and Hipp. While no systematic increases in latency were found, surprisingly, significant increases in P300-like ERP amplitude occurred in PFC and vHipp in the lesioned compared to the control rats. The implication of these findings for a rat model of Alzheimer’s disease will be discussed.

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Winter SS, Köppen JR, Stout JM, Cameron HA, Wallace DG, Cheatwood JL (2011) Growth factor infusion increases BrdU-positive cells in the denervated medial septum following 192-IgG-saporin lesion. Neuroscience 2011 Abstracts 331.04. Society for Neuroscience, Washington, DC.

Summary: During the progression of Alzheimer’s Disease, degeneration of basal forebrain structures is associated with a decline in mnemonic function and frequently results in episodes of wandering behavior. Previous work has demonstrated that the septohippocampal cholinergic system uniquely contributes to rat spatial orientation. Enhancement of endogenous adult neurogenesis represents one potential method to restore function to the septohippocampal system. Therefore, we tested the hypothesis that co-infusion of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) would increase the number of new cells in the medial septum following a lesion of the cholinergic system produced by focal injection of the ribosome-inactivating selective immunotoxin 192-IgG-saporin in rats. For this, rats received injections of 192-IgG-saporin into the medial septum. At the same time, a cannula was placed in the lateral ventricle and attached to a subcutaneously-placed osmotic minipump containing either 1) EGF, bFGF, and bromodeoxyuridine (BrdU), or 2) BrdU alone. Infusion of growth factors and BrdU continued for a period of two weeks, at which point the pumps were removed. At 21 days following 192-IgG-saporin injury, rats were perfused following standard protocols. Cryostat sections were collected at 40 microns and were processed via double-fluorescent immunochemistry (IHC) using antibodies against BrdU and doublecortin (DCX). Photomicrographs of BrdU and DCX immunofluorescence were captured under epifluorescence and the number of BrdU-positive and DCX-positive cells was quantified. We detected significantly higher numbers of BrdU-positive cells in the medial septum of rats that received growth factors compared to rats that received BrdU-only (p<0.05). These results indicate that infusion of growth factors following 192-IgG-saporin lesion of the medial septum resulted in an increase in the number of new immature neurons in the medial septum. Studies aimed at determining the fate of these young neurons and their influences on spatial orientation are ongoing.

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Pacheco-Herrero M, Thyssen D, Ramos-Rodriguez J, Berrocoso E, Bacskai B, Garcia-Alloza M (2011) Rapid beta-amyloid deposition and behavioural impairment after cholinergic denervation in APPswe/PS1dE9. Neuroscience 2011 Abstracts 47.02. Society for Neuroscience, Washington, DC.

Summary: Alzheimer’s disease (AD) is the most common cause of dementia. Although the ultimate neurotoxic mechanisms are not known, extensive evidence supports the role of amyloid-beta (Aβ) deposition as senile plaques (SP) in the disease. On the other hand, neuronal loss is the pathological feature that best correlates with the duration and severity of the illness and specifically, cholinergic denervation of the basal forebrain seems to be a good predictor of clinical dementia in AD. A close relationship has been documented between Aβ deposition and neurodegeneration, however, whether specific neurodegeneration may lead to senile plaque deposition remains unclear. We addressed this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p-75 saporin, an inmunotoxin that selectively removes cholinergic innervation. We performed intracerebroventricular murine p-75 lesions in animals with an incipient (~3 months) and robust (~7 months of age) Aβ deposition and removed ~50% of basal forebrain cholinergic innervation to cortex and hippocampus. Immediately after injections, cranial windows were implanted and Aβ deposition was monitored in vivo and in real time in the cortex using methoxy-XO4 and multiphoton microscopy. We observed increased SP deposition as soon as 1 week after the lesion. We further corroborated our in vivo data post-mortem, using anti- Aβ and anti-fibrils antibodies as well as thioflavin S staining, both in the cortex and the hippocampus. 7 days after the surgery, when the lesion is established, animals were tested in the new object discrimination and Morris water maze tests. We observed an early memory impairment in young lesioned mice (~3 months) and this effect worsened with age (~7 months of age), when Aβ deposition is more robust. Altogether, our data suggest that cholinergic denervation may contribute to the deposition of Aβ and synergistically contribute to the cognitive impairment observed in AD.

Related Products: mu p75-SAP (Cat. #IT-16)

Croxson PL, Kyriazis DA, Baxter MG (2011) Cholinergic modulation of a specific memory function of prefrontal cortex. Nat Neurosci 14(12):1510-1512. doi: 10.1038/nn.2971

Summary: The authors investigated loss of acetylcholine in the large and highly differentiated PFC’s of rhesus monkeys. The monkeys received 80-92 20-ng injections of ME20.4-SAP (Cat. #IT-15) per hemisphere. Lesioned animals were severely impaired on tasks involving spatial working memory.

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Angelucci F, Gelfo F, De Bartolo P, Caltagirone C, Petrosini L (2011) BDNF concentrations are decreased in serum and parietal cortex in immunotoxin 192 IgG-Saporin rat model of cholinergic degeneration. Neurochem Int 59(1):1-4. doi: 10.1016/j.neuint.2011.04.010

Summary: Brain-derived neurotrophic factor (BDNF) plays a role in neuronal function during the degeneration of neurons caused by pathological conditions such as Alzheimer’s disease. In order to investigate the relationship between brain and serum BDNF levels the authors administered 2 µg of 192-IgG-SAP (Cat. #IT-01) into each lateral ventricle of rats and measured brain and serum BDNF levels by ELISA. It was found that BDNF levels dropped in lesioned animals, but not until 15 days post surgery.

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Antonini V, Marrazzo A, Kleiner G, Coradazzi M, Ronsisvalle S, Prezzavento O, Ronsisvalle G, Leanza G (2011) Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. J Alzheimers Dis 24(3):569-586. doi: 10.3233/JAD-2011-101794 PMID: 21297260

Summary: Sigma-1 receptor agonists such as (-)-MR22 are potential therapeutic drugs for the treatment of cognitive and affective disorders. To model a cognitive disorder, rats received 81-ng bilateral injections of 192- IgG-SAP (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band of Broca, and 130-ng bilateral injections into the nucleus basalis magnocellularis. Lesioned animals also were treated with pre- aggregated amyloid peptide. Pretreatment with (-)-MR22 reversed cognitive impairments in the double-lesioned animals, indicating the potential use of sigma-1 receptor agonists as protective agents.

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Koppen JR, Winter SS, Cheatwood JL, Wallace DG (2010) Role of the septohippocampal GABAergic system in spatial orientation. Neuroscience 2010 Abstracts 806.16/KKK21. Society for Neuroscience, San Diego, CA.

Summary: Spatial orientation depends on the integrity of multiple neural systems. For example, during the progression of Alzheimer’s Disease, degeneration of the basal forebrain is associated with cognitive impairments including episodes of wandering. The medial septum projects both cholinergic and GABAergic fibers into the hippocampus. Research and therapies have typically focused on enhancing function of the cholinergic component; however, the GABAergic component has also been shown to contribute to hippocampal function. Previous attempts to characterize the role of the GABAergic system in spatial orientation involved non-selective lesion techniques in combination with the water maze task have failed to characterize the nature of the deficit mediating the impaired performance. Development of GAT1-Saporin immunotoxin provides a novel tool to selectively destroy GABAergic neurons in the medial septum. The current study examined the effects of injecting GAT1-Saporin or saline (sham lesion) into the medial septum on spatial orientation using the food-hoarding paradigm. The food-hoarding paradigm involves training rats to search for food pellets on a large circular table and carrying the food pellet directly to a visible refuge. Three probes dissociate the use of environmental and self-movement cues: 1) Hidden probe involved placing the refuge below the surface of the table, limiting rats to use distal environmental or self-movement cues to locate the refuge; 2) Dark Probe involved using the hidden refuge with the room lights off, limiting rats to use self-movement cues to locate the refuge; 3) New probe involved placing the hidden refuge on the opposite side of table, placing environmental and self-movement cues in conflict. Both sham and GAT1-Saporin rats were accurate in returning to the refuge during the Hidden probe. Only sham rats were accurate in carrying food to the refuge during the Dark probe. During the New probe, both groups initially carried the food pellet to the former refuge location. Although sham rats consistently carried the food pellet to the new refuge location after their initial error, GAT1-Saporin rats continued to perseverate to the former refuge location. The current study demonstrates a role for the septohippocampal GABAergic system in spatial orientation related to processing self-movement cues.

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Matchynski JJ, Lowrance SA, Rossignol J, Dekorver NW, Puckett ND, Pappas CA, Trainor KJ, Delongchamp JL, Radwan J, Heldt JC, Dey ND, Dunbar GL (2010) The effects of a combination of antioxidants and essential fatty acids as treatment for Alzheimer’s disease in the mu-p75 saporin-injected model. Neuroscience 2010 Abstracts 856.15/I21. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is marked by a progressive loss of memory and affects over five million people nationwide (Alzheimer’s Association, 2010). It is characterized by an increase in oxidative stress, amyloid plaques, neurofibrillary tangles, and the loss of cholinergic neurons. Mice injected with the ribosome deactivating protein, mu-p75 saporin, model the deficits in memory, loss of cholinergic neurons, and increased oxidative stress observed in AD. The current study aimed to decrease the deficits observed in the saporin mouse model using a combination of antioxidants from tart cherries and essential fatty acids, Cerise© total body rhythm (TBR). Mice dosed with TBR or methylcellulose were given bilateral ventricular injections of phosphate buffer saline or saporin. Memory and motor functioning were then measured in a series of behavioural tests. Results indicate that TBR decreased the memory deficits observed in object recognition, place recognition, and Morris-water-maze tasks, as well as the inflammatory response and loss of cholinergic neurons in the medial septum. The findings suggest that TBR could provide an effective, adjunctive treatment that may delay the onset or decrease the severity of AD.

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Lowrance SA, Matchynski JJ, Rossignol J, Dekorver N, Fink K, Salibi P, Dunbar GL (2010) Krx-0501 reduces cognitive deficits in a saporin mouse model of Alzheimer’s disease. Neuroscience 2010 Abstracts 856.8/I14. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disease marked by memory loss and dysfunction of cholinergic neurons. Neurotrophic factors, like nerve growth factor (NGF), have shown to improve cognitive function in AD patients. The inability of NGF to cross the blood brain barrier (BBB) and painful side effects have caused serious concerns over its future use as a treatment. Substituted pyrimidines, such as KRX-0501 (KRX; Keryx Biopharmaceuticals, New York, NY) on the other hand, readily cross the BBB and exert beneficial neurotrophic-like effects in vivo. In this study KRX was administered daily to mice that were given intra-cerebroventricular injections of mu p-75 Saporin (SAP; Advanced Targeting Systems, San Diego, CA) or vehicle (phosphate buffered saline). KRX treatment began at seven weeks of age and continued for 32 days. Doses were set at 10, 15, and 20mg/kg respectively. Animals were tested for cognitive impairment using the Morris water maze (MWM) task, object recognition (OR) and place recognition (PR) tasks while motor deficits were tested using MWM swim speed, rotarod (RR) and the open field (OF) tasks. On day 33 of KRX treatment, mice were sacrificed by transcardial perfusion. In a second experiment, mice received SAP or vehicle surgery and were sacrificed for enzyme-linked immunosorbent assay (ELISA) analysis. MWM results revealed significantly lower escape latencies of control animals relative to SAP animals. In addition mice treated with the low and middle doses of KRX displayed decreased escape latency on the MWM. In the OR task, only mice in the highest treatment group performed significantly above chance levels. No between group differences were seen in the PR task, swim speed, latency to fall from the RR, and distance travelled in the OF. Immunohistochemistry (IHC) using the glial fibrillary acidic protein antibody indicated that astrocyte activation took place primarily around the surgical injection sites. IHC labeling against choline-acetyltransferase revealed a significant decrease in cholinergic neurons of the medial septum. Finally, ELISA protein analysis of midbrain sections revealed that the KRX treatments did not increase levels of endogenous NGF. These results show that SAP injections produced a reproducible destruction of cholinergic neurons, accompanied by memory deficits in the MWM, in the absence of motoric deficits. The KRX treatment attenuated memory deficits, despite unabated cholinergic cell loss in the medial septum, and did so without affecting levels of endogenous NGF.

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Hammond R, Shinde A, Gibbs RB (2010) Effects of basal forebrain cholinergic lesions and estradiol on relative levels of estrogen receptor mRNAs in the rat forebrain. Neuroscience 2010 Abstracts 611.16/MMM67. Society for Neuroscience, San Diego, CA.

Summary: Beneficial effects of estradiol on cognitive performance are lost in response to cholinergic denervation of the hippocampus and frontal cortex. Effects of estradiol also decline with age and time following the loss of ovarian function, which parallels naturally-occurring declines in basal forebrain cholinergic function. We hypothesize that cholinergic impairment may alter the expression of estrogen receptors in specific regions of the brain, thereby decreasing estradiol effects. In the present study, quantitative RT-PCR was used to evaluate the effects of septal cholinergic lesions ± estradiol treatment on relative levels of three estrogen receptors, ERα, ERß, and GPR30. Young adult ovariectomized (OVX) rats received intraseptal injections of saline or 192 IgG-saporin (a selective cholinergic immunotoxin). One week later, rats received either silastic capsules containing 17ß-estradiol or a blank capsule, implanted s.c. Seven days later, rats were killed and the brains were dissected. Tissues from the hippocampus, frontal cortex, prefrontal cortex, striatum, and septum were collected. RNA was extracted and relative levels of ER mRNA determined. Levels within each sample were normalized to levels of GAPDH. Differences between treatments and controls were calculated using the ΔΔCt method. Preliminary data indicate that septal cholinergic lesions produced significant decreases in relative levels of ERα and ERß mRNA in the hippocampus, and an increase in ERß mRNA in the frontal cortex. Estradiol alone produced decreases in levels of ERα, ERß, and GPR30 mRNA in the frontal cortex, decreased levels of ERα and ERß mRNA in the septum, and increased levels of ERα mRNA in the striatum. In rats with cholinergic lesions that also received estradiol, decreased levels of ERα mRNA were detected in hippocampus and septum, and decreased levels of ERß mRNA also were detected in septum. Data suggest that some of the effects of cholinergic denervation on ER mRNA expression may be mitigated by estradiol treatment. These data show that cholinergic lesions significantly affect ER mRNA expression in the brain, and that effects are region-specific. Such effects could account for the loss of beneficial effects of estradiol on cognitive performance in association with age and time following menopause, as well as in association with specific neurodegenerative diseases such as Alzheimer’s disease.

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