alzheimers-disease

Nair DV, Al-Badri MM, Peng H, Pachego-Quinto J, Eckman CB, Iacono D, Eckman EA (2015) Preliminary investigation on the antidepressive effect of chronic oxotremorine treatment in a rodent model of Alzheimer’s disease. Neuroscience 2015 Abstracts 40.29/C34. Society for Neuroscience, Chicago IL.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the rate of progression varies from individual to individual. A great deal of evidence supports the idea that depression and other neuropsychiatric conditions co-exist with cognitive decline. However, the neurobiological basis of these symptoms and their influence on the clinical course of AD remain unclear. Our lab has shown previously that the 192-IgG saporin rat model of AD-like basal forebrain cholinergic cell loss exhibits a depression-like phenotype that develops months after the well-described impairment in spatial working memory. Furthermore, we have shown that chronic intracerebroventricular administration of the muscarinic agonist oxotremorine reverses both spatial working memory deficits and the depression-like behavior triggered by cholinergic denervation, and induces hippocampal neurogenesis. Current experiments are focused on determining additional pathological correlates of depression in this model and how they may be modulated by muscarinic agonists. To induce AD-like basal forebrain cholinergic cell loss, adult female Sprague Dawley rats were injected intracerebroventricularly (icv) with the immunotoxin 192-IgG-saporin (SAP) or saline as control (SHAM). After a 5 week recovery period, the rats received either 2 or 6 weeks of icv infusion of either oxotremorine or vehicle (saline) via osmotic minipump. Behavioral testing to assess the depressive phenotype was carried out using the sucrose consumption test every 2 weeks during oxotremorine treatment. The phenotype was further confirmed by forced swim test. The levels of ChAT, tryptophan hydroxylase (TPH), muscarinic receptors and FosB and ΔFosB were assessed in the hippocampus, basal forebrain, and orbitofrontal cortex by western blot and immunohistochemistry. Our preliminary results show increases in TPH, M1 receptors and FosB in the hippocampus, basal forebrain, and orbitofrontal cortex of a subset of treated animals, but no changes ChAT or ΔFosB. Further experiments are in progress to determine if there are changes in the expression of these and additional proteins in other brain regions including the nucleus accumbens, an area involved in activational aspects of motivation which also contributes to behavioral disorders such as to depression. The results of these studies may provide new insight in understanding the molecular basis of depression and antidepressant action of oxotremorine thereby defining new targets for possible therapeutic intervention for depressive symptoms in AD.

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Kim T, Thankachan S, McKenna J, McNally J, Yang C, Choi J, Chen L, Kocsis B, Deisseroth K, Strecker R, Basheer R, Brown R, McCarley R (2015) Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc Natl Acad Sci U S A 112:3535-3540. doi: 10.1073/pnas.1413625112

Summary: Measurements of cortical EEG capture gamma band oscillations (GBO). Abnormalities in these GBO have been found in some neuropsychiatric disorders such as Alzheimer’s disease and schizophrenia. The authors analyzed GBO neuronal groups by administering 650-ng bilateral icv injections of mu p75-SAP (Cat. #IT-16) to mice to determine the role of basal forebrain cholinergic neurons in the generation of GBO. The results indicate GABAergic basal forebrain neurons containing parvalbumin were important for GBO integrity, but cholinergic neurons in the basal forebrain were not involved.

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Nair DV, Al-Badri MM, Peng H, Schenkman N, Pacheco-Quinto J, Eckman CB, Iacono D, Eckman EA (2014) Chronic oxotremorine treatment ameliorates depressive phenotype in a rodent model of Alzheimer’s disease. Neuroscience 2014 Abstracts 670.03. Society for Neuroscience, Washington, DC.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative condition that is characterized by changes to brain structure and function. It is estimated that depression and other neuropsychiatric symptoms occur in up to 90% of AD patients, yet the neurobiological basis of these symptoms and their influence on the clinical course of AD remain unclear. Using a rat model of AD-like basal forebrain cholinergic cell loss, our lab has previously shown that central administration of a muscarinic receptor agonist, oxotremorine, for 4 weeks could induce hippocampal neurogenesis and reverse the spatial working memory deficit triggered by cholinergic denervation. Preliminary experiments conducted with this model in our lab also revealed a depressive phenotype emerging between 11 and 15 weeks after cholinergic denervation. The depressive phenotype was detected using a sucrose consumption test and further confirmed by forced swim test. The goal of the present study was to determine whether effects of chronic oxotremorine treatment could ameliorate the depressive phenotype observed after selective cholinergic cell loss in the basal forebrain. Adult female Sprague Dawley rats were injected intracerebroventricularly (icv) with the immunotoxin 192-IgG-saporin (SAP), to induce AD-like basal forebrain cholinergic cell loss. After a 5 week recovery period, the rats then received 8 weeks of icv infusion of either oxotremorine or vehicle (saline) via osmotic minipump. Behavioral testing to assess the depressive phenotype was carried out using the sucrose consumption test every 2 weeks during oxotremorine treatment. The phenotype was further confirmed by forced swim test. Biochemical analysis of a range of markers including tryptophan hydroxylase, the rate limiting enzyme for synthesis of serotonin, was performed after extraction of the brains following the behavioral tests. Results of these experiments demonstrate that oxotremorine treatment prevents the development of the depressive phenotype in SAP-lesioned rats. A number of oxotremorine-treated rats showed increases in tryptophan hydroxylase, suggesting a possible mechanism for the improved behavioral phenotype Based on these data, we propose that 192-IgG saporin lesioned rats may be an effective model for studying the pathophysiology and therapeutic modulation of age- and neurodegeneration-related neuropsychiatric symptoms such as depression.

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Köppen JR, Stuebing SS, Sieg M, Blackwell AA, Blankenship P, Grisley ED, Cheatwood JL, Wallace DG (2014) Is selective hippocampal cholinergic deafferentation sufficient to produce temporally graded retrograde amnesia?. Neuroscience 2014 Abstracts 749.20. Society for Neuroscience, Washington, DC.

Summary: Dementia of the Alzheimer’s type (DAT) is a neurodegenerative disorder marked by degeneration of basal forebrain structures and is associated with significant mnemonic deficits. The current study used a rat string-pulling task to evaluate whether selective cholinergic deafferentation of the hippocampus is sufficient to produce temporally graded retrograde amnesia. Female rats were pre-trained to pull strings to obtain reinforcement (cashew). Subsequently, rats were trained to discriminate between two scented strings. One scented string was consistently reinforced (+A), while the other scented string was never reinforced (B). After rats met criterion, they either waited two weeks (recent) or six weeks (remote) prior to receiving a sham surgery or infusion of 192-IgG-Saporin into the medial septum. Two weeks later rats were given four days of reversal training during which they experienced the same scented strings; however, the cashew was at the end of the string that was not previously reinforced. Following reversal training, rats were trained on a novel discrimination (+C/D). The results of the current study are consistent with selective cholinergic deafferentation of the hippocampus being sufficient to produce retrograde amnesia that was not temporally graded. First, all rats met criterion in a similar number of days. Rats receiving infusion of 192-IgG-Saporin into the medial septum had a higher number of correct responses during reversal training, relative to sham rats; however, no group differences were observed between recent and remote groups. Next, there were no group differences in the ability to learn a new discrimination. Finally, no group differences we observed in the latency to approach and pull up the string. The results were not caused by deficits in motivation or motor function, but they do reflect impairments in mnemonic function. The current study provides a novel behavioral assessment technique that models the retrograde amnesia characteristics observed in DAT.

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Van Kampen JM, Kay DG, Maelicke A (2014) The galantamine prodrug, Memogain®, reverses deficits in hippocampal neurogenesis associated with the loss of basal forebrain cholinergic neurons. Neuroscience 2014 Abstracts 789.21. Society for Neuroscience, Washington, DC.

Summary: Loss of basal forebrain cholinergic innervation of the hippocampus and severe neuronal loss within the hippocampal CA1 region are early hallmarks of Alzheimer’s disease (AD), and are strongly correlated with cognitive status. This loss of cholinergic innervation is a key factor underlying alterations in hippocampal neurogenesis, which are also characteristic of AD. We have previously reported the effects of various cholinergic compounds on hippocampal neurogenesis indicating that acetylcholine serves as a potent neurogenic regulator. Memogain® (GLN 1062) is an inactive galantamine pro-drug with 15 fold higher brain availability than galantamine. It is designed to provide improved blood brain barrier penetration, greater potency, and fewer side effects than the cholinesterase inhibitors currently used for the treatment of Alzheimer’s dementia. This would serve both to promote patient adherence and permit the use of higher doses. Galantamine is unique among the cholinesterase inhibitors in that it also has allosteric actions at α-7 nicotinic receptors, activation of which has been linked to both disease-modifying and cognitive enhancing effects, as well as effects on hippocampal cell proliferation. Here, we describe the neurogenic actions of Memogain® in a rodent model of cholinergic depletion. Infusion of the immunotoxin, 192IgG saporin (SAP), used to induce selective basal forebrain cholinergic cell loss reminiscent of that found in AD, resulted in a pronounced loss of basal forebrain cholinergic neurons and hippocampal ChAT fiber density. Consistent with earlier reports, SAP-lesioned animals had significantly fewer BrdU+ and PCNA+ cells in both the dentate gyrus and CA1 region of the hippocampus, when compared to sham-operated control animals. These animals also displayed significant impairments in spatial working memory, as assessed by a T-maze and the radial arm maze. By contrast, animals treated with Memogain® displayed a restoration of hippocampal cell proliferation, increased neuronal cell counts, normalized neuronal migration, and improvements in cognitive function. Thus, the beneficial effects of Memogain® may extend beyond acute cognitive enhancement, to include disease modification through support of hippocampal neurogenesis.

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Tiwari D, Haynes J, Short J, Pouton C (2014) Investigating the potential of stem cell based therapy in an immunotoxin mouse model of Alzheimer’s disease. Neuroscience 2014 Abstracts 295.14. Society for Neuroscience, Washington, DC.

Summary: Purpose: To characterize a dual reporter embryonic stem (ES) cell line and validate an immunotoxin mouse model of Alzheimer’s disease for future transplantation experiments. Methods: A dual (mcherry and Lhx8+) reporter ES cell line was derived from E14Tg2a mouse ES cells assessed for differentiation capability and characterized using immunocytochemistry. For the immunotoxin model, 6-8 weeks C57BL/6 male mice (n = 12) were treated with bilateral intracerebroventricular injections of saline or mu-p75-saporin toxin (0.4µg/µl/mouse) to cause cholinergic neuronal lesions. Mice were cognitively assessed using a novel water maze (WM) protocol and novel object recognition (NOR) paradigm. Immunohistochemistry was performed to detect toxin dependent neuronal loss. Results: A significant difference in learning the WM task was observed during cued and spatial trials, with toxin-treated mice showing longer latency to platform than controls (two way ANOVA; p<0.01). Also performance during probe trial was significantly reduced in treated mice (t-test; p<0.05), indicating memory loss by toxin. No memory impairment was detected using the NOR test. Immunohistochemistry for choline acetyltransferase (ChAT) confirmed a significant loss (p<0.001; t test) of cholinergic neurons in the medial septum. These data indicate that the model is appropriate for future transplantation studies. FACS analysis of reporter cell line showed a small population of Lhx8+ cells at day 6 and 10 of differentiation. Immunocytochemistry for ChAT on day 18 cells revealed few cholinergic positives neurons as compared to wild type controls. Conclusion: Literature suggests a possible role of Lhx8 in cholinergic development and these cells are being further investigated by transplantation.

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Llorente A, Gonzalez De San Roman E, Moreno M, Manuel I, Giralt M, Rodriguez R (2014) Activity mediated by neurolipid (CB1 and LPA1) and neuropeptide (GAL1) receptors in a rat model with cholinergic basal forebrain lesion. Neuroscience 2014 Abstracts 307.25. Society for Neuroscience, Washington, DC.

Summary: The cholinergic basal forebrain neurons (CBFN) which innervate cortical, hippocampal and amygdaloid areas, control learning and memory processes and are damaged in Alzheimer´s disease. An intraparenquimal injection of the 192IgG-saporin (SAP) immunotoxin, specifically eliminates CBFN. The present study examined the activity of endocannabinoid (CB1), lysophosphatidic acid (LPA1), galanin (GAL1) and muscarinic (MR) receptors, measuring Gi/o protein activation by [35S]GTPγS autoradiography in rats after the selective cholinergic basal forebrain lesion. CB1 immunoreactivity (CB1-ir) was also analyzed in the SAP administration area. We observed a high CB1-ir in the basal forebrain of the lesioned rats. The autoradiographic assays revealed that WIN55,212-2 (10 μM) evoked stimulation (CB1 activity) was increased in lateral olfactory tract (data expressed in % stimulation over basal; CSF vs SAP; 55 ± 11% vs 128 ± 13%, p<0.05) and in entorhinal cortex (156 ± 17% vs 277 ± 30%, p<0.01), but decreased in hippocampal dentate gyrus (299 ± 37% vs 166 ± 21%, p<0.05) and in medial amygdala (116 ± 20% vs 50 ± 7%, p<0.05). LPA (10 μM) induced stimulation (LPA1 activity) showed an increase in the internal capsule (60 ± 10% vs 137 ± 19%, p<0.01). The MR activity that was measured using carbachol (100 μM) was increased in hippocampal dentate gyrus (27 ± 6% vs 62 ± 7%, p<0.05) and in entorhinal cortex (55 ± 10% vs 94 ± 11%, p<0.05) but decreased in the nucleus basalis of Meynert (nbM) (46 ± 10% vs 15 ± 6%, p<0.05). Finally, there was an increased stimulation (GAL1 activity) of galanin (1 μM) in the nbM (45 ± 13% vs 80 ± 12%, p<0.05). The CB1-ir and GAL1 activity was increased in the lesioned area where the cholinergic neurotransmission was impaired, indicating a possible neuroprotective action on the surviving CBFN.

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Manuel I, Llorente A, Gonzalez de San Roman E, Merino L, Giralt M, Rodriguez-Puertas R (2014) Memory and cholinergic impairment using a new approach of bilateral lesion of rat cholinergic basal forebrain. Neuroscience 2014 Abstracts 134.02. Society for Neuroscience, Washington, DC.

Summary: The cholinergic basal forebrain neurons (CBFN), which innervate cortical, hippocampal and amygdaloid areas control learning and memory processes and are damaged in Alzheimer´s disease (AD). The aim of the present study was to characterize the model of selective induced CBFN death in the nucleus basalis of Meynert (nbM) of adult Sprague-Dawley rats by intraparenquimal injection of the specific CBFN immunotoxin 192IgG-saporin (SAP) (n=11; 1μl/side [135ng/μl]). Learning and memory behavior was evaluated with the passive avoidance (PA) test. The CBFN density and the presence of glial cells were evaluated by immunofluorescence (P75NTR, Neu-N, GFAP, Iba-1). The AChE activity and AChE+ neuron density were analyzed by staining reaction. A significant decrease in CBFN (P75NTR -ir) density was observed in SAP treated rats (-82,7% vs aCSF, p<0,001). We found that cognitive impairment in the PA test and the reduction in the CBFN density in nbM correlated with each other (P75NTR+-ir vs PA, r2=0,51, p<0,05). Similar results were obtained for the reduction in AChE staining in cortical areas (entorhinal cortex: r2=0,55, p<0,01), hippocampus (CA3 pyramidal: r2=0,49, p<0,01) and amygdala (anterior: r2=0,43, p<0,01). Immunofluorescence studies showed a high density of activated microglia (Iba-1-ir) and an abscence of astrocytes (GFAP-ir) in the SAP administration area. Moreover, using MALDI-IMS assay, some lipid species were modified around the lesion area in SAP treated rats. The obtained data on the above described model of CBFN death, mimics the cognitive and cholinergic system impairment described in AD patients.

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Hartig W, Saul A, Kacza J, Grosche J, Goldhammer S, Michalski D, Wirths O (2014) Immunolesion-induced loss of cholinergic projection neurones promotes beta-amyloidosis and tau hyperphosphorylation in the hippocampus of triple-transgenic mice. Neuropathol Appl Neurobiol 40(2):106-120. doi: 10.1111/nan.12050

Summary: 3xTg transgenic mice were treated with 2 μg of mu p75-SAP (Cat. #IT-16) into the right lateral ventricle to eliminate cholinergic neurons in the basal forebrain. These mice already have age-dependent β-amyloidosis and tau hyperphosphorylation. This new model supplies a potential framework in which to study the entire pathology of Alzheimer’s disease.

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Laursen B, Mork A, Plath N, Kristiansen U, Frank Bastlund J (2014) Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration. Brain Res 1543:253-262. doi: 10.1016/j.brainres.2013.10.055

Summary: The Tg2576 mouse strain provides a limited model for Alzheimer’s disease because they do not display degeneration of cholinergic neurons in the basal forebrain – the other main hallmark of Alzheimer’s disease in humans. Using 0.9 μg icv injections of mu p75-SAP (Cat. #IT-16) the authors evaluated mice that had both Aβ deposition and cholinergic depletion. The data show that these mice display cognitive decline and compromised cholinergic levels, creating a viable model for Alzheimer’s disease.

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