alzheimers-disease

Jeong D, Lee J, Lee S, Kim S, Chang J (2012) Spatial memory facilitation by electrical stimulation of the medial septum in rats. Neuroscience 2012 Abstracts 851.01. Society for Neuroscience, New Orleans, LA.

Summary: Recently, deep brain stimulation has been used to treat various neurological disorders. Some studies support that DBS can be a strategy to treat Alzheimer’s disease. The aim of this study was to evaluate the effect of electrical stimulation in the medial septum using rat model mimicking basal forebrain cholinergic deficits of Alzheimer’s disease. Four experimental groups were composed of normal, lesion, lesion + implantation and lesion + stimulation. 192 IgG-saporin (Selective cholinergic toxin, 8ul of 0.63ug/ul) were bilaterally injected into the lateral ventricle. Electrode was stereotactically implanted into the left medial septum (AP +0.6, ML 0.16, DV -6). Stimulation parameters are 50Hz, 120us pulse width and 1 volt. One week after implantation, Stimulation started for 2 weeks. Two weeks after surgery, water maze was performed for 1 week and rats were sacrificed immediately after behavioral test. Features were verified by immunochemistry and AChE assay. During the training trials, latencies of lesion and implantation significantly increased in day3 and day4. In contrast, latency of stimulation group had no differences as compared to normal group but it decreased significantly when compared to lesion group in day4. In the probe test, lesion group had decreases in time in target quadrant, time in platform zone and the number of platform crossing. Although they did not perform as normal group, stimulation group showed tendency of recovery. IHC and AChE assay are ongoing. Spatial memory is associated with hippocampus. We had expected activation of hippocampus by stimulation of the medial septum. We confirmed that stimulation of the medial septum facilitates acquisition and recall of spatial memory. Currently we are studying the effects of medial septal stimulation on the hippocampus.

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Anderson ML, Govindaraju KP, Shors TJ (2012) Acetylcholine and Learning: Are they related and does it matter for associating events across time?. Neuroscience 2012 Abstracts 600.12. Society for Neuroscience, New Orleans, LA.

Summary: Decades ago, acetylcholine was considered intrinsic to processes related to attention and/or learning and memory. Much of this was based on its presumed role in dementia associated with Alzheimer’s disease. However, in the last decade or so, this relationship has been questioned and with good reason (Parent & Baxter, 2004). That said, only a few studies have addressed the involvement of acetylcholine in tasks that require an animal to associate stimuli separated in time, such as trace eyeblink conditioning. This type of task is dependent on the hippocampus and is severely disrupted in both patients with Alzheimer’s disease and animal models of the disorder (Kishimoto, 2012; Waddell et al., 2008; Woodruff-Pak & Papka, 1996). In the present study, we hypothesized that animals with minimal Ach input to both hippocampi would not learn whereas those with input into one hippocampus could. The immunotoxin 192 IgG-Saporin was infused into the MSDB to selectively kill cholinergic neurons in Sprague-Dawley rats and then trained with either delay or trace eyeblink conditioning. Delay conditioning requires that the stimuli during training are contiguous in time and is not dependent on the hippocampus. Animals were given 200 trials for four days for 800 trials in total. A complete bilateral MSDB-cholinergic lesion was considered complete if the number of neurons that express choline acetyltransferase was reduced by 75 %. A bilateral lesion of this magnitude prevented early acquisition of the trace response (p<.05). Indeed, none of the animals so far trained reached a learning criterion of 60 % CRs during any session of training. In contrast, animals with a loss of ACh in just one hemisphere were able to learn the CR. Furthermore, preliminary data suggest delay conditioning was unaffected by the loss of ACh from the septum. Finally, animals with half the number of cholinergic neurons were still able to learn trace eyeblink conditioning regardless of whether the damage was bilateral or unilateral. Thus, it would appear that the progressive loss of ACh coincides with the loss of learning potential, especially when that learning requires associations across time. This approach and the experimental results may model the progressive nature of Alzheimer’s disease, in which the loss of neuronal function is slow but cumulative.

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Lee J, Jeong D, Chang J (2012) The effects of basal forebrain cholinergic neuron of recognition tests. Neuroscience 2012 Abstracts 345.10. Society for Neuroscience, New Orleans, LA.

Summary: The cholinergic neurons of the Medial septum and the basal nucleus areas of the basal forebrain project to the frontal cortex and the Hippocampus, and degeneration of the cholinergic basal forebrain neuron is a common feature of Alzheimer’s disease(AD) and vascular dementia and it has been correlated with cognitive decline. This research studied to verify the effects of cholinergic neuron in basal forebrain and the role of hippocampus and frontal cortex on recognition through recognition test and immunohistochemistry after damaging cholinergic neuron of the basal forebrain by intraventricular injection of 192 IgG-saporin. 192 IgG-saporin of 8ul (0.63ug/ul) was injected to the bilateral lateral ventricle of rats. After 2 weeks, Novel object recognition (NOR) test and Object in place (OIP) test was conducted to elucidate damage of cholinergic neuron. After completing the behavioral test, the ChAT cholinergic neuron in the brain was ascertained to confirm with immunohistochemistry if cholinergic neuron was damaged. In NOR test, the lesion group with 192 IgG-saporin showed 10% lower novel object preference than normal group. In OIP test, the normal group showed 50% novel object preference and the lesion group with 192 IgG-saporin showed 30% novel object preference in an hour delay test. On the other hand, the normal group and the lesion group with 192 IgG-saporin shoed 33% and 35% novel object preference respectively in a day delay test. However, this rate is not that significant value enough to elucidate behavioral difference between normal group and lesion group. In immunohistochemistry, the number of cholinergic neuron was remarkably decreased in basal forebrain. According to both of the behavioral tests, lesion group seem to less remember novel object than normal group. Also, they searched less the novel object that changed its location than normal group in the short term condition. However, there was no significant difference in the long term condition. These results suggest that the lesion with 192 IgG-saporin can damage spatial working memory.In the Immunohistochemistry result of the lesion condition, cholinergic input to hippocampus in basal forebrain affects recognition. However, the effect is not so essential.

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Lee S-Y, Ma J, Chung C, Han J-S (2012) Effects of chronic stress on alterations of GR-PKA-NF-kappa B signaling and spatial learning in rats with cholinergic deafferentation. Neuroscience 2012 Abstracts 345.20. Society for Neuroscience, New Orleans, LA.

Summary: Aging and Alzheimer’s disease (AD) is associated with diminished integrity of the cholinergic innervations of the hippocampus and cortex. Previously, we demonstrated that removal of the cholinergic innervations impaired regulation of the HPA axis with response to acute stress and induced changes in the interaction among glucocorticoid receptor (GR), nuclear factor-κB (NF- κB) p65, and the cytoplasmic catalytic subunit of protein kinase A (PKAc) in the hippocampus. The current research examined effects of chronic stress on the altered signaling induced by cholinergic deafferentation. Young adult rats received immunotoxic lesions of basal forebrain cholinergic neurons by intracranial injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band and substantia innominata/nucleus basalis. After 2 weeks recovery from surgery, rats with cholinergic lesions and vehicle-injected control rats were subjected to 1 hr restraint stress per day for 2 weeks. Rats with only cholinergic deafferentation or sham-operated rats with chronic stress showed intact spatial learning. Rats with cholinergic deafferentation that received chronic stress showed impairments of spatial learning. And we examined that cholinergic deafferentation induced alterations in GR and NF- κB p65 expression in hippocampus and prefrontal cortex. Thus the loss of cholinergic integrity during aging and in AD may increase proneness to chronic stress.

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Nichols TW (2012) Emerging roles of pathogens in alzheimer’s and moderate magnetic field therapy: dc emf 0.5 tesla. Neuroscience 2012 Abstracts 438.10. Society for Neuroscience, New Orleans, LA.

Summary: Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer disease (AD) and various types of spirochete (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type-1 (HSV-1). (Miklossy 2011 Exp Rev Mol Med) Miklossy’s lab exposed mammalian glia & neuronal cells in vitro to Borrelia burgdorferi spirochetes and bacterial lipopolysaccharides (LPS). Morphological changes analogous to amyloid deposits were observed at 2-8 wks exposure. Increased levels of ß-amyloid precursor protein and hyperphosphorylated tau were detected by WB.The frequency of spirochetes is significantly higher in the brains of Alzheimer patients compared to controls.The statistical analysis is based on the cumulative data of the literature. (P=1.5×10-17,OR=20, 95%CI=8-60! Seven out of ten brains from the Harvard McLean Brain bank were positive for Borrelia DNA. Alan Mac Donald MD. “Borrelia Infection is the root cause of at least 70% of Alzheimer’s disease, based on the detection of positive In situ DNA hybridization results in the cytoplasic GVB sites of hippocampal neurons ( with no positive signals detected in the nucleus) for flagellin B DNA sequences of Borrelia burgdorferi.” Antibiotics in Alzheimer’s disease: A randomized controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease 2004. Cognitive decline was statically improved in treatment over placebo. Minocycline protects basal forebrain cholinergic neurons from mu p 75-saporin immunotoxic lesioning 2004 in animal model. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models 2007. Minocycline does not affect amyloid ß phagocytosis by human microglia cells. (Minocycline attenuates the release of TNF-α by human microglia upon exposure to Abeta, SAP and C1q) 2007. Moderate Magnetic Field Therapy (0.5 Tesla) in 15 Alzheimer’s patients. Results; Cognition Improved: group average hours = 184.Mechanism hypothesis: Overview of crosstalk between SMF & IL-6.Wang, Z, Sarje A, Che PL, Yarema K. Moderate strength (0.23-0.28T) static magnetic fields (SMF) modulate signaling and differentiation in human embryonic cells. BMC Genomic 2009;10:356

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Mathis C, Moreau P-H, Zerbinatti C, Goutagny R, Cosquer B, Geiger K, Kelche C, Cassel J-C (2012) Combined loss of entorhinal and basal forebrain cholinergic hippocampal inputs deeply impairs spatial navigation memory in C57BL/6J and hAPPxapoE mice. Neuroscience 2012 Abstracts 203.28. Society for Neuroscience, New Orleans, LA.

Summary: The hippocampus plays a key role in spatial learning and memory. Major inputs provided by the cholinergic basal forebrain (CBF) and the entorhinal cortex (EC) neurons are expected to modulate hippocampal functions. Surprisingly, the selective lesion of one or the other produces only moderate performance degradation in spatial navigation tasks, suggesting possible compensation provided by other hippocampal inputs. We therefore assessed the effects of single versus combined lesions of the EC (NMDA excitotoxin) and the CBF (mu-p75 saporin immunotoxin) on several forms of memory in C57BL/6 mice. Single lesions had moderate or no effects, while the combined lesions completely abolished long-term spatial memory retention in the water-maze and the Barnes-maze navigation tasks. Object recognition memory was selectively and profoundly affected by the loss of cholinergic neurons, whereas object location memory was only marginally affected by the lesions. These results suggest that the integrity of both the CBF and the EC is critical to establish an enduring spatial navigation memory. The synergistic interaction between the two lesions is particularly relevant to Alzheimer’s disease (AD) since both structures undergo severe degeneration in parallel to dramatic impairments in spatial navigation tasks. The apolipoprotein E4 (apoE4) allele, a major genetic risk factor for AD, has been proposed as a cholinergic deficit predictor and has been associated with larger EC atrophy in AD patients. Thus, the effects of single and combined EC and CBF lesions were evaluated on Barnes maze navigation performance in hAPPxapoE mice knocked-in for the human apoE3 or apoE4 gene allele on a (normal) human APP YAC transgenic background. Long-term spatial memory performances of hAPPxapoE3 and hAPPxapoE4 mice were dramatically affected by the CBF lesion and the combined lesions, but not by the EC lesion. A similar pattern of deficit was observed on learning performances in apoE4 not in apoE3 mice; the latter were only affected by the combined lesions. In conclusion, the apoE4 genotype had no effect on the consequences of EC and combined lesions, but it worsened the outcome of CBF lesions compared to the apoE3 genotype. Since the mice of the two genotypes showed similar loss of cholinergic neurons, our data may reflect a deleterious impact of apoE4 on the activity of the few surviving neurons (about 20%). Alternatively, our findings would also be consistent with impaired compensatory mechanisms following cholinergic loss which could depend on other hippocampal inputs such as the entorhinal cortex. Further analyses are underway to clarify this issue.

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Koppen JR, Winter SS, Stuebing SL, Cheatwood JL, Wallace DG (2013) Infusion of GAT1-saporin into the medial septum/vertical limb of the diagonal band disrupts self-movement cue processing and spares mnemonic function. Brain Struct Funct 218(5):1099-1114. doi: 10.1007/s00429-012-0449-7

Summary: Both mnemonic and spatial processing are adversely affected by dementia due to Alzheimer’s disease. There is evidence to support the involvement of cholinergic systems in this deficit. In this work the authors examined how GABAergic neurons in the septohippocampus contribute to these cognitive functions. Rats received a total of 350 ng of GAT-1-SAP (Cat. #IT-32) infused into the medial septum-diagonal band of Broca. Although lesioned animals performed normally in tasks involving spatial cues, food hoarding was affected indicating that self-movement cue processing was interfered with by the loss of these GABAergic neurons.

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Gil-Bea FJ, Gerenu G, Aisa B, Kirazov LP, Schliebs R, Ramirez MJ (2012) Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice. Neurobiol Dis 48(3):439-446. doi: 10.1016/j.nbd.2012.06.020

Summary: The hallmarks of Alzheimer’s disease (AD) include hippocampal cell loss, cholinergic dysfunction, amyloid plaques, and neurofibrillary tangles, among other things. This work sought to examine the interaction between cholinergic denervation, amyloid precursor protein (APP) processing, and hippocampal integrity. Tg2576 transgenic mice received 2 μg of mu p75-SAP (Cat. #IT-16) injected into the third ventricle. These mice overexpress a version of human APP. Lesioned animals displayed various aspects of AD such as hippocampal synaptic pathology and neurodegeneration, indicating that immunolesions in this mouse line produce a viable model for AD.

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Lowrance S, Matchynski J, Rossignol J, Dekorver N, Sandstrom M, Dunbar G (2012) CXB-909 attenuates cognitive deficits in the mu-p-75 saporin mouse model of Alzheimer’s disease. Neuroscience & Medicine 3(1):65-68. doi: 10.4236/nm.2012.31010

Summary: CXB-909 is a small molecule NGF amplifier that has been shown to enhance neurite outgrowth in various neuronal cell lines. This type of molecule has potential therapeutic use in disorders such as Alzheimer’s disease. In this work the authors lesioned cholinergic cells in the basal forebrain of mice with bilateral 0.8 μg intracerebroventricular injections of mup75-SAP (Cat. #IT-16). Lesioned animals performed significantly worse than controls in a water maze task. Lesioned animals subsequently treated with CXB-909 displayed improved performance, indicating that CXB-909 can attenuate memory deficits caused by loss of cholinergic input.

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Lee J, Jeong D, Chang J (2011) The effects of basal forebrain cholinergic neuron on novel object recognition. Neuroscience 2011 Abstracts 878.10. Society for Neuroscience, Washington, DC.

Summary: Medial septum and basal nucleus areas of the basal forebrain project cholinergic neurons to the frontal cortex and the Hippocampus.And degeneration of the cholinergic basal forebrain neurons is a common feature of Alzheimer’s disease (AD) has been correlated with cognitive decline. This research was studied to verify the effects of cholinergic neuron in basal forebrain to the role of the hippocampus and the frontal cortex on recognition through recognition test and immunohistochemistry after damaging cholinergic neuron of the basal forebrain by intraventricular injection of 192 IgG-saporin. 192 IgG-saporin of 8ul (0.63ug/ul) was injected to the bilateral lateral ventricle of rats. After 2 weeks, novel object recognition (NOR) test was conducted to elucidate damage of cholinergic neuron. In the NOR test, rats are exposed to two identical objects for 15 minutes in empty plastic box (60cmx60cmx30cm). After 3 hours, they are reintroduced to the same object and a new novel object for 10 minutes. This procedure was repeated for 4 days After completing the behavioral experiment, the ChAT of cholinergic neuron in the basal forebrain was ascertained to confirm with immunohistochemistry if cholinergic neuron was damaged. In NOR test, the lesion group with 192 IgG-saporin showed 10% lower novel object preference than normal group. However, this rate is not that significant value enough to elucidate behavioral difference between normal group and lesion group. In immunohistochemistry, the number of cholinergic neuron was remarkably decreased in basal forebrain. According to both of the NOR test and Immunohistochemistry in the condition under lesion, Cholingergic input to hippocampus and frontal cortex from basal forebrain affects recognition somewhat, however the effect is not so essential.

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