alzheimers-disease

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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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.

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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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