Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system

Torres, Eduardo Miguel; Perry, TracyAnn; Blokland, Arjan; Wilkinson, Lawrence S.; Wiley, Ronald G.; Lappi, Douglas A.; Dunnett, Stephen B.

doi:10.1016/0306-4522(94)90010-8

Cited by 328 publications

(245 citation statements)

References 65 publications

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“…[31][32][33] This immunotoxin has been used extensively to study the behavioral and neurochemical sequelae of cholinergic hypofunction, but its influence on surviving neurons remains unclear. [32][33][34][35][36] In the present study, we report that 192-IgG-saporin-induced loss of basal forebrain cholinergic neurons is accompanied by a time-dependent increase in the levels of the CI-MPR as well as other markers of the EL system in neurons of the affected areas that survive the immunotoxin treatment. These results provide the very first evidence that upregulation of the CI-MPR and EL system may act as an adaptive mechanism to restore metabolic and structural abnormalities in neurons that survive toxicity/injury.…”

supporting

confidence: 48%

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Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

Hawkes

Kabogo

Amritraj

et al. 2006

The American Journal of Pathology

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The cation-independent mannose 6-phosphate receptor (CI-MPR) is a single transmembrane domain glycoprotein that plays a major role in the trafficking of lysosomal enzymes from the trans-Golgi network to the endosomal-lysosomal (EL) system. Because dysfunction of EL system is associated with a variety of neurodegenerative disorders, it is possible that the CI-MPR may have a role in regulating neuronal viability after toxicity/injury. In the present study, we report that 192-IgG-saporin-induced loss of basal forebrain cholinergic neurons causes a transient upregulation of CI-MPR protein levels in surviving neurons of the basal forebrain and frontal cortex but not in the brainstem region, which was relatively spared by the immunotoxin. This was accompanied by a parallel time-dependent increase in other EL markers, ie, cathepsin D, Rab5, and LAMP2 in the basal forebrain region, whereas in the frontal cortex the levels of cathepsin D, and to some extent Rab5, were increased. Given the critical role of the EL system in the clearance of abnormal proteins in response to changing conditions, it is likely that the observed increase in the CI-MPR and components of the EL system in surviving neurons after 192-IgG-saporin treatment represents an adaptive mechanism to restore the metabolic/structural abnormalities induced by the loss of cholinergic neurons.

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supporting

confidence: 48%

“…However, the cholinergic neurons that survived the immunotoxin treatment were found not to express the p 75NTR (Figure 4, G, H, K, and L). Additionally, CI-MPRpositive cholinergic neurons in the brainstem, which are also p 75NTR -negative, 31,34 did not show any significant alterations in receptor expression in the treated rats.…”

Section: -Igg-saporin and Ci-mprmentioning

confidence: 76%

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

Hawkes

Kabogo

Amritraj

et al. 2006

The American Journal of Pathology

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mentioning

confidence: 73%

“…saporin [15,23,30]. The verification and extent of the lesion are commonly assessed by post-mortem measuring of different biochemical markers, such as AChE [1,29], ChAT [24,33] or high-affinity choline uptake (HACU) [26].…”

mentioning

confidence: 99%

“…Partial cortical cholinergic deafferentiation was achieved by intraparenchymal infusion of the selective cholinergic immunotoxin, 192 IgG-Saporin, into the NBM [15,30]. It has been described that this immunotoxin, at the concentration used in the present work, produces maximal depletion of cortical cholinergic markers, sparing other non-cholinergic neuronal populations [3,7,22,30]. Under this experimental condition, a significant decrease in cholinergic function was achieved, as reflected by significant decreases in different cholinergic markers in the frontal cortex of lesioned animals, similar to those previously described after this type of lesion [4,25,36].…”

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confidence: 99%

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Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit

Gil-Bea

García-Alloza

Domínguez

et al. 2005

Neuroscience Letters

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Cognitive deficits in neuropsychiatric disorders, such as Alzheimer's disease (AD), have been closely related to cholinergic deficits. We have compared different markers of cholinergic function to assess the best biomarker of cognitive deficits associated to cholinergic hypoactivity. In post-mortem frontal cortex from AD patients, acetylcholine (ACh) levels, cholinacetyltransferase (ChAT) and acetylcholinesterase (AChE) activity were all reduced compared to controls. Both ChAT and AChE activity showed a significant correlation with cognitive deficits. In the frontal cortex of rats with a selective cholinergic lesion, all cholinergic parameters measured (ACh levels, ChAT and AChE activities, "in vitro" and "in vivo" basal ACh release) were significantly reduced. AChE activity was associated to ChAT activity, and even more, to "in vivo" and "in vitro" basal ACh release. Quantification of AChE activity is performed by an easy and cheap method and therefore, these results suggest that determination of AChE activity may be used as an effective first step method to evaluate cholinergic deficits.

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Selective changes in hippocampal neuropeptide Y neurons following removal of the cholinergic septal inputs

et al. 1997

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The number and distribution of subpopulations of hilar interneurons containing neuropeptide Y (NPY), somatostatin (SOM), or gamma-aminobutyric acid (GABA) immunoreactivities were examined in the hilus of the dentate gyrus following removal of the cholinergic septal inputs. One, 2, 4, 8, 12, and 24 weeks after intracerebroventricular injections of immunotoxin, consisting of antibody to the low-affinity nerve growth factor receptor conjugated to saporin (192 IgG-saporin), lesioned rats were processed simultaneously with controls for NPY, SOM, or GABA immunolabeling. Across all time points, the number of NPY-labeled neurons was reduced to a statistically significant level (paired t-test, P = 0.001) in the injected rats (73% of control values, on average). The decrease in the number of NPY-labeled neurons was not limited to any particular subregion rostrally but appeared greater in the central region caudally. The size of NPY-labeled neurons did not differ statistically between control and immunolesioned rats examined at 1, 2, and 24 week time points. In contrast, the number of both SOM- and GABA-immunoreactive neurons in injected rats did not appear to be affected in any consistent manner. Examination of the hilus in adjacent Nissl-stained sections with the optical dissector revealed that although the total number of small nonprincipal cells (5-15 microm in diameter) did not appear affected at the 4-week time point, there was a statistically significant (P = 0.03) reduction across the 8-24-week time points (to 80% of control values, on average). Dual-labeling studies on separate rats showed that a small subpopulation of the NPY- and SOM-labeled neurons, primarily in the infragranular hilus, were colocalized with neurons containing GABA immunoreactivity (18% and 5%, respectively). These studies demonstrate that removal of the cholinergic septal inputs (1) can cause relatively rapid, selective decreases in the number of NPY-immunoreactive hippocampal interneurons and (2) appears to lead to the death of hippocampal interneurons over a longer time course. The changes in NPY immunoreactivity seem to occur in the portion of interneurons that probably does not contain either SOM or GABA immunoreactivity.

show abstract

Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system

Cited by 328 publications

References 65 publications

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit

Selective changes in hippocampal neuropeptide Y neurons following removal of the cholinergic septal inputs

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