alzheimers-disease

Lee KY, Leos R, Borowski TB, de Lacalle S (2001) Bcl-2 improves survival of lesioned cholinergic neurons. Neuroscience 2001 Abstracts 803.6. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease is associated with the progressive cell death of cholinergic neurons in the central nervous system (CNS). A current challenge is to develop therapeutic approaches that could prevent atrophy and loss of CNS neurons, and promote regeneration of their processes. The purpose of our study is to determine the therapeutic potential of the antiapoptotic gene B-cell lymphoma 2 (bcl-2) on the cholinergic system of the basal forebrain (BF). Retrograde degeneration in the BF of 3-month-old rats was induced by unilateral injection of the immunotoxin 192 IgG-saporin into the entorhinal cortex. Fifteen minutes later, an injection of 5 µg of the pa22bgala4bcl-2 plasmid was placed into the BF. Similar procedures were followed for BF injections of a control plasmid or vehicle alone. We found that a single injection of bcl-2 plasmid into the BF of the lesioned side increased survival of cholinergic neurons ~50%, as compared to vehicle controls. In addition, cell survival was close to 100% of intact side with bcl-2 injections, compared to a 50% cell loss in animals injected with a control DNA. Our results indicate that an injection of the bcl-2 gene into the BF prevents loss of cholinergic neurons that have been injured by IgG-saporin. Mechanisms by which bcl-2 may protect cholinergic neurons could include retrograde transport of the plasmid to the nucleus and subsequent neuroprotective effects of increased levels of bcl-2 protein. Our results, in conjunction with other studies, suggest that neurodegeneration might be amenable to gene therapy.

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

Harrell LE, Kolasa K, Parsons DS, Conger K (2001) α-1 adrenergic agonist effect on cholinergic muscarinic receptors. Neuroscience 2001 Abstracts 549.16. Society for Neuroscience, San Diego, CA.

Summary: Degeneration of the basal forebrain cholinergic system and sympathetic ingrowth appear to be pathological changes in Alzheimer’s Disease patients (AD), leading to an alteration in the balance between both systems and may mediate cognitive deficits in AD. In an attempt to model this situation, intraventricular injection (ivc) of a specific cholinergic immunotoxin, 192-IgG-saporin, has been used to induce peripheral noradrenergic fibers to grow into cortex and hippocampus after cholinergic denervation of rat cortex (CCD) and hippocampus (HCD). This adrenergic reorganization has been termed cortical (CSI) and hippocampal (HSI) sympathetic ingrowth. 192-IgG-saporin ivc injection was followed by intraperitoneal (ip) treatment with α1 agonist methoxamine. Thus the effects on choline acetyltransferase (ChAT) activity, norepinephrine (NE) level and muscarinic acetylcholine receptors (mAChR) were studied in rat hippocampal and cortical brain tissue. We found that 192-IgG-saporin produced significant decrease in ChAT activity in all experimental groups and areas. Methoxamine (3 and 6 mg/kg ip) did not affect NE levels. It produced significant decrease in mAChR affinity in the cholinergic denervation group and no significant increase in mAChR density in cholinergically denervation groups of dorsal hippocampal and cortical areass. Results of the present study indicate the influence of α1 agonist treatment on mAChR and may provide new concepts for the future combination drug therapy for AD patients.

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

Kolasa K, Harrell LE, Parsons DS, Conger K (2001) α-1 adrenergic antagonist effect on cholinergic muscarinic receptors. Neuroscience 2001 Abstracts 549.17. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic denervation of cortex and hippocampus in rat causes an unusual neuronal rearrangement, in which peripheral sympathetic fibers, originating from superior cervical ganglia, grow into the cholinergically denervated areas. This process has been termed cortical (CSI) and hippocampal sympathetic ingrowth (HSI). A similar process may occur in Alzheimer’s Disease (AD). Recent studies suggest that the balance between central adrenergic and cholinergic systems may be important for normal learning and memory, while the alterations of these systems may play a critical role in cognitive deficits of AD. To better understand this situation specific cholinotoxin, 192-IgG-saporin, was intraventricularly (ivc) injected to produce a selective loss of cholinergic cells in rat basal forebrain nuclei, cholinergically denervating hippocampal (HCD) and cortical areas (CCD). This effect was confirmed by significant decrease in choline acetyltransferase activity in all groups and brain structures.192-IgG-saporin injection was followed by a treatment with α1-adrenergic antagonist prazosin to determine the effect on hippocampal and cortical muscarinic acetylcholine receptors (mAChR) and norepinephrine (NE) level. Prazosin (0.5 & 2 mg/kg ip) produced decreases in NE levels of HSI and CSI and induced no significant increase in mAChR affinity in HSI and CSI groups in dorsal hippocampus,anterior and entorhinal cortex. Injected at the dose of 2 mg/kg it increased mAChR density in CSI of both cortical areas. The present results began to define the interaction between adrenergic and cholinergic systems, as α1 antagonist treatment affects mAChR,a potential therapeutic target in AD.

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

Hartonian I, de Lacalle S (2001) Long-term plastic changes in galanin innervation in rat basal forebrain. Neuroscience 2001 Abstracts 254.1. Society for Neuroscience, San Diego, CA.

Summary: Galanin (GAL) immunoreactive (-ir) fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer’s Disease (AD), perhaps exacerbating the cholinergic deficit. The purpose of our study is to determine whether a similar hyperinnervation of GAL-ir fibers occurs following intraparenchymal injection of 192-IgG saporin, a specific cholinergic neurotoxin, within the horizontal diagonal band of Broca (HDB), in 3-month-old rats, and to identify its origin. Immunotoxic lesions produced on average a 31% reduction in cholinergic cell counts on the lesioned side versus the spared side. Hyperinnervation of GAL-ir fibers was observed within and adjacent to the HDB in 28 out of 36 rats, and this effect persisted across time, with 6 months being the longest time examined. Morphometry revealed an increase in the number of GAL-ir cells on the lesioned basal forebrain, as compared to control. A similar change could not be detected in the number of GAL-ir neurons in the amygdala or the bed nucleus of the stria terminalis. Although there was no significant correlation in the amount of cell loss and of GAL hyperinnervation, we suggest that GAL hyperinnervation is triggered by the loss of cells because it is persistent across time. Our data suggests that this hyperinnervation is the result of overexpression of GAL in some cholinergic neurons of the basal forebrain. Since GAL is known to inhibit acetylcholine release, exacerbating the cholinergic dysfunction in AD, this model can be useful to test the efficacy of GAL inhibitors.

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

Savage LM, Buzzette R, Ramirez D (2001) The role of the cholinergic basal forebrain in learning, memory and reward expectancies. Neuroscience 2001 Abstracts 314.18. Society for Neuroscience, San Diego, CA.

Summary: The cholinergic basal forebrain degenerates in Alzheimer’s Disease and the degree of this degeneration correlates with a decline in cognitive processing. In the present study we have modeled this degeneration in the rat by the selective immunotoxin 192 IgG-Saporin. This immunotoxin destroys cholinergic neurons in the basal forebrain nuclei in rats and thus allows for the study of the impact of cholinergic deafferentation on learning, memory, and other cognitive processes without direct effects on other neuronal systems. After intracerebroventricularly infusions of the immunotoxin or vehicle solution, male rats were allowed to recover for three weeks before being tested in a matching-to-position task. The matching-to-position task was altered to influence the type of cognitive strategies a subject would use to solve the task. The main behavioral manipulation was the use of the differential outcome procedure (DOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition. We found that cholinergic lesions did not dramatically impair learning the matching rule. However, the memory performance of subjects with cholinergic lesions was dramatically impaired – if subjects were not trained with the DOP. When subjects were trained with the DOP, and relied on reward expectancies to solve the delayed-matching-to-position task the cholinergic lesion had little effect. These findings demonstrate that cholinergic immunolesions by 192IgG-saporin induce specific cognitive impairments—dependent on task demand characteristics.

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

Hamaue N, Yamazaki Y, Ohmori H, Sumikawa K (2001) Nicotine enhances N-methyl-D-aspartate receptor responses and facilitates long-term potentiation in the hippocampus from rats with cholinergic lesions. Neuroscience 2001 Abstracts 376.5. Society for Neuroscience, San Diego, CA.

Summary: Nicotine reverses cognitive impairments caused by lesion of the cholinergic system and improves performance of Alzheimer’s patients. The mechanisms underlying these effects of nicotine, however, are unknown. Because nicotine facilitates the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in the hippocampal CA1 region, we examined whether nicotine enhances NMDAR responses and facilitates LTP induction in the hippocampus from rats with cholinergic lesions. Selective cholinergic denervation of rat hippocampus was performed by the immunotoxin 192 IgG-saporin. We then recorded burst NMDAR responses in hippocampal slices prepared from 192-IgG-saporin-treated rats and found that nicotine (1 μM) enhanced burst NMDAR responses. When GABAergic transmission was completely blocked by picrotoxin, nicotine had no effect on burst NMDAR responses. We also monitored the induction of LTP in 192-IgG-saporin-treated hippocampi and found that a weak tetanus (20 pulses at 100 Hz), which induced LTP in PBS-treated hippocampi, failed to induced LTP. However, in the presence of nicotine (1 μM), a same weak tetanus induced LTP in 192-IgG-saporin-treated hippocampi. Our results suggest that nicotine potentiates NMDAR responses by disinhibition of pyramidal cells and facilitates LTP induction in the hippocampus from animals with cholinergic lesions. The observed nicotine effects may represent the cellular mechanism underlying the compensatory action of nicotine in the presence of cholinergic deficits.

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

de Butte M, Fortin T, Sherren N, Pappas BA (2001) Selective neonatal neurochemical lesions persist into old age and cause Alzheimer-like pathology. Neuroscience 2001 Abstracts 426.8. Society for Neuroscience, San Diego, CA.

Summary: There is a strong negative correlation between forebrain acetylcholine (ACH) function and the depth of Alzheimer’s dementia (AD). Forebrain norepinephrine (NE) is also frequently reduced in AD. However, it is not clear when these neurochemical abnormalities begin. Since there is some evidence to suggest that the AD begins early in life but fulminates with aging, it may also be the case that ACH and/or NE dysfunction occurs early and participates in the slide towards dementia in old age. To shed light on this possibility, we created lesions of forebrain ACH and NE in the neonatal rat by intracranial injection of 192 IgG saporin and systemic injection of 6-OHDA respectively, allowing the animals to reach old age. Massive ACH and NE lesions were evident at 22 months of age as reflected by immunohistochemical probes for p75 low affinity nerve growth factor and dopamine beta hydroxylase immunoreactive axons respectively. Morris water maze testing showed that surprisingly, the NE but not the ACH lesioned rats were impaired on this reference memory task. Typically, young NE lesioned rats are not impaired on it. The ACH lesion did not exacerbate the consequences of the NE lesion. On the other hand, unbiased stereological counts of hippocampal CA1 pyramidal cells indicated that the ACH lesion caused a significant loss of cells whereas the NE lesion had no effect by itself nor did it exacerbate the effects of the ACH lesion. These results indicate that selective NE and ACH lesions inflicted at birth, persist into old age. Furthermore, the NE lesion seemingly impairs memory in old age while the ACH lesion causes a loss of CA1 cells reminiscent of that which is a hallmark of AD.

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

Yan J, Price DL, Koliatsos VE (2001) Nestin expression in neurons of the medial septum/diagonal band in the adult rat. Neuroscience 2001 Abstracts 25.9. Society for Neuroscience, San Diego, CA.

Summary: Nestin is a marker for neuronal precursor cells in normal animals. In adult animals, nestin (+) cells are limited to the ventricular wall, hippocampus and the rostral migratory stream, where neurogenesis is known to persist throughout life. We are now reporting the existence of nestin (+) cells in the medial septum/diagonal band area based on immunocytochemical staining with different nestin antibodies. Many of these cells colocalize ChAT and nestin. In addition, some nestin (+) cells can be traced with the carbocyanin dye SP-DiI injected into the lateral ventricle to label cell lineages originating in the ependymal layer. Medial septal/diagonal band lesions by complete fimbria-fornix transections or 192-IgG-saporin conjugate injections into the ventricle cause an increase in BrdU (+) and nestin (+) cells in medial septum/diagonal band especially in anterior planes. We are currently double labeling the sections with BrdU and nestin or TUJ1. Our working hypothesis is that there may be ongoing neurogenesis in the medial septum/diagonal band in the adult brain, especially after injury or under pathological conditions and this may have implications for pathogenesis and treatment of Alzheimer’s disease.

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

Berger-Sweeney JE, Stearns NA, Murg SL, Floerke-Nashner LR, Lappi DA, Baxter MG (2001) Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior. J Neurosci 21(20):8164-8173. doi: 10.1523/JNEUROSCI.21-20-08164.2001

Summary: 192-Saporin (Cat. #IT-01) has long been an effective agent for elimination of cholinergic neurons in the basal forebrain of rats. Until the development of mu p75-SAP (Cat. #IT-16) there was no equivalent agent for use in mice. The authors tested mu p75-SAP in vitro and in vivo (1.8-3.6 µg in right lateral ventricle), using cytotoxic, histochemical, and behavioral assays. The data shows that mu p75-SAP is a highly selective and efficacious lesioning agent for cholinergic neurons in the mouse. The authors conclude that mu p75-SAP will be a powerful tool to use in combination with genetic modification to investigate cholinergic damage in mouse models of Alzheimer’s disease.

Related Products: mu p75-SAP (Cat. #IT-16), 192-IgG-SAP (Cat. #IT-01)

Hartlage-Rübsamen M, Schliebs R (2001) Sequential upregulation of cell adhesion molecules in degenerating rat basal forebrain cholinergic neurons and in phagocytotic microglial cells. Brain Res 897(1-2):20-26. doi: 10.1016/s0006-8993(01)02093-5

Summary: Neurodegeneration, found in brain disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, is marked by a significant microglial response. This microglial activation is characterized by increased migratory activity and potential cytotoxic action on injured neurons. The interaction of microglial cells with degenerating axons and neural somata is known to be mediated by expression of cell adhesion molecules. The authors use a single intracerebroventricular injection of 192-Saporin (4 µg; Cat. #IT-01) to initiate neurodegeneration of choline acetyltransferase-immunoreactive neurons and follow the expression of two cell adhesion molecules, ICAM-1 and LFA-1, using immunohisto-chemistry. The results indicate that these adhesion molecules may function as intercellular recognition signals through which degenerating cholinergic neurons actively participate in their own targeting and removal by microglia.

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