alzheimers-disease

Quinlivan M, Chalon S, Vergote J, Henderson J, Katsifis A, Kassiou M, Guilloteau D (2007) Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning. Neurosci Lett 415(2):97-101. doi: 10.1016/j.neulet.2006.08.065

Summary: The vesicular acetylcholine transporter (VAChT) is a useful imaging target to assess Alzheimer’s disease, since this transporter is expressed on cholinergic cells that are lost as the disease progresses. Through the use of 192-IgG-SAP (Cat. #IT-01) the authors demonstrate the use of two radioligands, one that binds VAChTs, the other which binds nicotinic acetylcholine receptors (nAChRs). The results show the efficacy of each radioligand, as well as the loss of nAChRs on cholinergic neurons after treatment with 192-IgG-SAP.

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

Van Kampen JM, Eckman CB (2006) Cholinergic agonists restore deficits in hippocampal neurogenesis after basal forebrain lesions in the adult rat brain. Neuroscience 2006 Abstracts 674.13. Society for Neuroscience, Atlanta, GA.

Summary: Discrete regions of the adult CNS, including the dentate gyrus of the hippocampus, retain the capacity for neurogenesis. Progenitor cells in these regions may represent a potential source of endogenous cells for replacement therapies in neurodegenerative diseases. In order to facilitate the development of such therapeutic approaches, an understanding of the microenvironmental signals regulating neurogenesis in the adult brain is essential. Small molecule neurotransmitters, such as acetylcholine, have been shown to regulate neurogenesis both during development and in the adult brain. In the studies presented here, we examine the effects of various cholinergic agonists on hippocampal neurogenesis in the adult rat brain. Intraventricular administration of a nicotinic agonist significantly attenuated proliferation, while muscarinic agonists triggered a dose-dependent increase in neurogenesis within the dentate gyrus and CA1 regions of the hippocampus. This effect was blocked by the M1 receptor-selective antagonist, pirenzepine. The basal forebrain provides an abundant source of cholinergic input to the hippocampus, thought to play an important role in learning and memory and Alzheimer’s disease (AD) pathophysiology. Loss of this cholinergic innervation, as occurs in AD, was achieved by a selective immunotoxin and resulted in a significant reduction in hippocampal neurogenesis. This loss of neurogenesis was reversed by intraventricular administration of a muscarinic receptor agonist. The loss of basal forebrain cholinergic inputs observed in AD may contribute to deficits in learning and memory through reductions in hippocampal neurogenesis. The results reported here suggest that pharmacological manipulation of the cholinergic system may represent a means of stimulating hippocampal neurogenesis as a potential treatment strategy.

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

Ho N, Han S, Dawe GS (2006) Effect of running on neurogenesis in cholinergic lesioned mice. Neuroscience 2006 Abstracts 318.5. Society for Neuroscience, Atlanta, GA.

Summary: Neurogenesis occurs mainly in two regions of the adult rodent brain, the dentate gyrus of the hippocampus and the subventricular zone. There are many factors which regulate neurogenesis, but voluntary exercise has consistently been shown to enhance neurogenesis. Exercise has been reported to specifically stimulate neural cell proliferation in the hippocampus but not the olfactory bulb. One of the major sources of afferents to the hippocampus are the septohippocampal projections, in which axons from the medial septum and diagonal band of Broca (MSDB) project to the hippocampus. Major components of the septohippocampal pathway that act as ‘pacemakers’ for hippocampal theta rhythm, which increases in conjunction with the voluntary running, are the cholinergic and GABAergic projections rising from cells in the MSDB. This present study investigates the effect of a partial cholinergic lesion in the basal forebrain and MSDB of mice, a partial model of the neurodegeneration that occurs in Alzheimer’s disease, on neural cell proliferation and neurogenesis. Murine p75-SAP, a conjugate of a p75 antibody that targets selectively cholinergic cells and cytotoxic saporin, was injected into the ventricles of female adult Swiss mice. After recovery from surgery mice were then administered bromodeoxyuridine (BrdU). BrdU immunopositive cells were quantified 24 hours and 4 weeks to assess for neural cell proliferation and survival of newly generated cells. Partial cholinergic denervation led to a decrease in the survival of new born cells in the dentate gyrus. We compared the effects of voluntary running for a period of 12 days in non-lesioned and lesioned mice under similar experimental conditions. Running resulted in an increase in neural cell proliferation for both the non-lesioned and lesioned groups. Running led to a marked increase in cell proliferation in lesioned mice compared to the controls, and also enhanced neurogenesis, as determined by the colocalization of BrdU and the neuronal nuclei marker NeuN in cells within the dentate gyrus. The present study suggests that voluntary running may have a positive effect on neurogenesis in neurodegenerative models in rodents. Further work needs to be done to elucidate the underlying mechanisms of exercise-induced neurogenesis.

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

Chauhan NB (2006) Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 brain. Neuroscience 2006 Abstracts 271.8. Society for Neuroscience, Atlanta, GA.

Summary: Today’s Alzheimer’s disease (AD) research lacks a “complete” model that would represent both plaque and tangle pathology together with correlative memory deficits. Although currently developed transgenic model including APP/PS1/tau mutations do not “truly” represent AD because tangles observed in AD brain are independent of tau mutations. Subtly increased β-amyloid (Aβ) levels either due to familial mutations or sporadic causes, primarily targets pre-tangle cytopathology and degeneration of basal forebrain cholinergic neurons (BFCN) via deranged signaling of glygogen synthase kinase 3-beta (GSK3β)-, protein kinase A (PKA)-, and extracellular signal-regulated kinase (ERK2) of ERK-mitogen-activated protein kinase (MAPK) cascade, leading to reduced phosphorylation of cAMP responsive element binding protein (CREB) that results in synaptic and memory deficits much earlier than the emergence of classic AD-pathology. Thus, subtly elevated Aβ, together with BFCN deficits resulting from Aβ-induced deranged signaling, set up a vicious feedback loop to produce characteristic plaque- and tangle-pathology observed in AD. Based on these facts, we wished to test if selective lesioning of basal fore brain cholinergic neurons during the early stages of amyloid build-up will exacerbate tau phosphorylation and produce tangle-like inclusions in transgenic mice with APP mutations. We produced selective immunotoxic lesions of BFCN by injecting the BFCN-specific cholinergic immunotoxin, which is known to specifically target p75-expressing BFCN and spare p75-expressing cerebellar neurons (Mu-p75-Saporin, Advanced Targeting Systems, #IT-16), intracerebroventricularly (ICV) in TgCRND8 mice harboring Swedish (KM670/671NL) and Indiana (V717F) mutations. This model exhibited tangle-like inclusions, provoked already existing plaque pathology, and worsened already impaired behavioral deficits.

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

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Scattoni ML, Adriani W, Calamandrei G, Laviola G, Ricceri L (2006) Long-term effects of neonatal basal forebrain cholinergic lesions on radial maze learning and impulsivity in rats. Behav Pharmacol 17(5-6):517-524. doi: 10.1097/00008877-200609000-00018

Summary: Work in the last decade has focused on clarifying the role of cholinergic dysfunction in Alzheimer’s disease. 7 day-old rats received 0.21 µg of 192-Saporin (Cat. #IT-01) administered to the third ventricle, and were tested at 5 months of age in delay tolerance and a radial maze. Test results suggest that prolonged basal forebrain cholinergic hypofunction is detectable only when using highly complex tasks.

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

Traissard N, Herbeaux K, Cosquer B, Jeltsch H, Ferry B, Galani R, Pernon A, Majchrzak M, Cassel JC (2007) Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer’s Disease: Effects on locomotor activity and memory functions in rats. Neuropsychopharmacology 32(4):851-871. doi: 10.1038/sj.npp.1301116

Summary: Two characteristics of Alzheimer’s disease (AD) are cholinergic dysfunction in the basal forebrain, and neuronal damage in the entorhinal cortex. Using 5 µg intracerebroventricular (icv) injections of 192-IgG-SAP (Cat. #IT-01), and 2.3 µg icv injections of OX7-SAP (Cat. #IT-02), locomotor activity, working, and reference memory of rats were examined. Although 192-IgG-SAP lesions caused limited deficits, rats receiving both lesions exhibited several behaviors associated with AD. The authors suggest that combining these lesions may be a more accurate model for AD than 192-IgG-SAP alone.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02)

Kolasa K, Parsons D, Harrell LE (2005) Time-dependent neurotrophins effect on cholinergic denervation and hippocampal sympathetic ingrowth following 192 IgG-saporin lesioning of medial septum. Neuroscience 2005 Abstracts 1004.4. Society for Neuroscience, Washington, DC.

Summary: In rat,injection of specific cholinotoxin,192 IgG-saporin into the medial septum results not only in a selective denervation of hippocampus(CD),but in an ingrowth of peripheral sympathetic fibers,originating from the superior cervical ganglion,into the hippocampus.This process has been termed hippocampal sympathetic ingrowth(HSI).A similar process,in which sympathetic noradrenergic axons invade hippocampus,may also occur in Alzheimer’s disease(AD). The severity of cognitive decline in AD patients has been linked to multiple factors including cholinergic and neurotrophic factors and their receptors,which undergo selective alterations throughout the progression of AD.It is known that the sites of synthesis of NGF(nerve growth factor),BDNF(brain derived-neurotrophic factor)and LIF (leukemia inhibitory factor)in rat septo-hippocampal system are predominantly hippocampal neurons.By using 192 IgG-saporin we have been able to mimic some of the cardinal features of AD e.x.cholinergic denervation and hippocampal sympathetic ingrowth and to study their effect on neurotrophins in dorsal hippocampus.Thus,2,8,and 12 weeks after injection of 192 IgG-saporin we measured NGF, BDNF and LIF protein and mRNA expression using Western blot and RT-PCR techniques, respectively.Choline acetyltransferase activity(ChAT) and norepinephrine(NE) concentration was also detected. Significant alterations were found in NGF and LIF protein expression(decrease at 8 weeks and increase at 12 weeks post lesions)in HSI group. Significant decrease of BDNF(mature form) protein expression was found in CD group over whole period of time. There was significant decrease found in BDNF mRNA expression in CD,with normalization in HSI group 12 weeks post lesions. Results of the study suggest that neurotrophins are affected by cholinergic denervation and may play an important role in regulation and development of HSI,which might be a beneficial phenomenon for restoration at least some of cognitive function.

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

Pedersen AF, Kostova V, Christensen E, Veng LM, Lohals R, Knudsen GM, Aznar S (2005) Intraventricular IgG192-saporin lesions lead to altered 5-HT2A receptor levels in the hippocampus. Neuroscience 2005 Abstracts 559.17. Society for Neuroscience, Washington, DC.

Summary: Background: Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder in humans. One of the traits of the disease is the presence in the brain of beta-Amyloid plaques and loss of cholinergic neurons in the basal forebrain. Other transmittersystems especially serotonin may be involved in the patophysiology of AD. Clinical studies have observed a higher incidence of depression among AD patients and a higher risk of developing dementia when diagnosed with major depression. It is known that serotonin and serotonin receptors, among them 5-HT2A receptors (5-HT2AR), are involved in depression. Interestingly, recent PET-studies have shown lower 5-HT2AR levels in entorhinal cortex and hippocampus in early stages of AD. Objectives: Our aim was to investigate whether 5-HT2AR levels were affected in the hippocampus after lesioning the cholinergic neurons in the basal forebrain, thereby highlighting a possible interaction between the serotonergic and the cholinergic transmitter systems. Methods: Intraventricular injection of 5ug IgG192-Saporin or saline in adult Wistar male rats. After 20 weeks the rats were sacrificed and the hippocampus were isolated. After homogenisation the levels of 5-HT2AR were determined by western blot. Results: Downregulation of the 5-HT2AR levels were observed after 20 weeks. 5-HT2AR levels for animals receiving IgG192-Saporin for 1, 2 and 4 weeks will also be investigated. Conclusion: Our results show a direct effect of cholinergic lesions on hippocampal 5-HT2AR. This may be explained by a compensatory effect of the serotonergic system for the loss of cholinergic input as there may be a balance between these two systems in the hippocampus.

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

Yamazaki Y, Jia Y, Hamaue N, Sumikawa K (2005) Nicotine-induced switch in the nicotinic cholinergic mechanisms of facilitation of long-term potentiation induction. Eur J Neurosci 22(4):845-860. doi: 10.1111/j.1460-9568.2005.04259.x

Summary: The authors investigated cellular mechanisms underlying improved cognitive function in Alzheimer’s disease patients upon the administration of nicotine. To model Alzheimer’s disease in rats, 2 µg of 192-IgG-SAP (Cat. #IT-01) was injected into the lateral cerebral ventricle. Examination of the lesioned animals suggests that nicotine promotes the induction of long-term potentiation by enhancing N-methyl-D-aspartate responses, and suppressing acetylcholine-mediated mechanisms in pyramidal cells.

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

Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM (2005) Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus. Neuropathol Appl Neurobiol 31(4):395-404. doi: 10.1111/j.1365-2990.2005.00655.x PMID: 16008823

Related Products: Quinolinic Acid Rabbit Polyclonal, Conjugated (Cat. #AB-T095)