alzheimers-disease

Dudkin KN, Chueva V, Makarov FN, Bich TG, Roer AE (2005) Impairments in working memory and decision-taking processes in monkeys in a model of Alzheimer’s disease. Neurosci Behav Physiol 35(3):281-289. PMID: 15875490

Related Products: ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03)

Gil-Bea FJ, Garcia-Alloza M, Dominguez J, Marcos B, Ramirez MJ (2005) Evaluation of cholinergic markers in Alzheimer’s disease and in a model of cholinergic deficit. Neurosci Lett 375(1):37-41. doi: 10.1016/j.neulet.2004.10.062

Summary: Several markers of cholinergic function may be able to predict cognitive deficits due to disorders such as Alzheimer’s disease. The authors compared baseline measurements of acetylcholine, cholinacetyltransferase, and acetylcholinesterase (AChE) of rats against animals treated with 0.067 µg injections of 192-Saporin (Cat. #IT-01) into both hemispheres of the nucleus basalis magnocellularis. The results indicate that measurement of AChE activity is an inexpensive and reliable method to evaluate cholinergic function in rats as well as in humans.

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

Leung LS, Petropoulos S, Ma J, Shen B (2004) Cholinergic neurons in the basal forebrain participate in consciousness and general anesthesia. Neuroscience 2004 Abstracts 565.4. Society for Neuroscience, San Diego, CA.

Summary: Acetylcholine (Ach) in the brain has long been associated with consciousness. In this study, we assessed consciousness in rats by their EEG and behavioral responses to a general anesthetic. Cholinergic neurons in the nucleus basalis of Meynert (NbM) were lesioned by bilateral injection of toxin IgG192-saporin (0.15 μg at P1.4, L2.7, 7.7 mm below dura) in 10 adult male rats. Control (5 rats) had saline injected into the NbM. EEGs were recorded by electrodes placed in layer V of the frontal cortex (FC) and visual cortex (VC). Spectral analysis of the spontaneous EEGs in FC and VC during awake-immobility indicated that lesioned animals showed higher delta (0.8 to 4 Hz) and lower gamma (30- 58 Hz) power as compared to controls. Subsequent acetylcholinesterase staining (optical density) confirmed significant Ach depletion in both FC and VC, in the lesion as compared to the control group (P<0.002, Wilcoxon). When challenged with a normally subanesthetic dose of general anesthetic, the lesioned rats showed, as compared to controls, significantly longer durations of loss of righting and tail-pinch response after 5 mg/kg i.v. propofol (P<0.001), but not after 20 mg/kg i.p. pentobarbital or 2% halothane. In correspondence with the deep behavioral anesthesia, delta power at FC after propofol was significantly larger in lesioned than control rats. Lesioned rats, as compared to controls, also showed decreased locomotion (behavioral excitation) when given 2% halothane in a large chamber. In summary, a loss of Ach in the neocortex decreases the level of consciousness as indicated by increased delta and decreased gamma EEG, and by an increased sedative/ anesthetic response to propofol i.v. We suggest that patients with Alzheimer disease may show altered response to some general anesthetics.

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

Hawkes CA, Kar S (2004) Loss of basal forebrain cholinergic neurons by 192 igG-Saporin induces increased IGF-II/M6P receptor expression in select brain areas. Neuroscience 2004 Abstracts 92.1. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is characterized neuropathologically by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss in selected brain areas, including basal forebrain cholinergic neurons, which project to the hippocampus and neocortex. Increasing evidence supports a role of the endosomal-lysosomal (EL) system in the pathophysiology of AD. A key component of the EL system is the insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor, a single transmembrane domain glycoprotein which functions in the intracellular trafficking of lysosomal enzymes, and in the internalization of extracellular IGF-II and M6P-containing ligands. However, very little is known about the functional significance of this receptor in the brain. We examined expression of the IGF-II/M6P receptor and other markers of the EL system, at different time points following bilateral i.c.v. injection of 192 IgG-saporin. 192 IgG-saporin produced an almost complete loss of ChAT-positive neurons in the basal forebrain, as well as fibers in the hippocampus and frontal cortex, while striatal cholinergic neurons were unaffected. Western blotting and immunocytochemistry results indicate an upregulation of IGF-II/M6P receptor levels in the septum and frontal cortex. A modest increase was also observed in cathepsin D levels. The level of other EL markers, such as Rab5 and LAMP1, showed varied temporal and spatial changes. These results suggest that brain areas innervated by basal forebrain neurons, respond differently to the loss of cholinergic input and that elements of the EL system may be involved in cholinergic degeneration/compensatory responses of surviving neurons.

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

Kar S, Hawkes C, Jhamandas JH (2004) Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin induces activation of glycogen synthase kinase-3β activity. Neuroscience 2004 Abstracts 92.2. Society for Neuroscience, San Diego, CA.

Summary: Glycogen synthase kinase-3β (GSK-3β) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is negatively regulated by phosphorylation of Ser9 and upregulated by Tyr216 phosphorylation. Activation of GSK-3β induces apoptosis in a variety of cultured neurons and the inhibitory control of its activity by Akt kinase is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192-IgG saporin was used to address the potential role of GSK-3β in the degeneration of the basal forebrain cholinergic neurons which are preferentially vulnerable in Alzheimer’s disease (AD) brain. Our results show that GSK-3β colocalizes with a subset of the forebrain cholinergic neurons and that loss of these neurons is accompanied by a transient decrease in phospho-Akt and phospho-Ser9 GSK-3β levels in the basal forebrain, hippocampus and the cortex. Neither total Akt, GSK-3β, nor phospho-Tyr216 GSK-3β levels were significantly altered in the aforesaid brain regions of treated animals. These results provide the very first evidence that increased GSK-3β activity is associated with in vivo degeneration of the forebrain cholinergic neurons and thus may be involved in the loss of these neurons as observed in AD brains.

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

Kolasa K, Parsons D, Conger K, Harrell LE (2004) Neurotrophic modulation of cholinergic denervation and hippocampal sympathetic ingrowth following immunolesioning with 192 IgG-saporin. Neuroscience 2004 Abstracts 92.9. Society for Neuroscience, San Diego, CA.

Summary: Injection of specific cholinotoxin, 192 IgG-saporin into the medial septum (MS)of rat induces not only a selective cholinergic denervation of hippocampus (CD),but an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion,into the hippocampus (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 neurotrophin synthesis in the 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 study their effect on growth factors in dorsal hippocampus. Thus,12 weeks after injection of 192 IgG-saporin we measured neurotrophic protein and mRNA expression using Western blot and RT-PCR techniques,respectively. Choline acetyltransferase activity(ChAT)and norepinephrine(NE) concentration was also detected.There was no change in NGF,BDNF,NT3,GDNF mRNA expression,but we have found significant decrease in 240 bp and increase in 328 bp of persephin mRNA expression in CD, and “normalization” in HSI group. No significant alteration was found in NGF and persephin protein expression, but significant decrease in mature form of BDNF protein expression was found in CD, with “normalization”in HSI group.Results of the study suggest that growth factors 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 of at least some cognitive function.

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

Ricceri L, Minghetti L, Moles A, Popoli P, Confaloni A, De Simone R, Piscopo P, Scattoni ML, di Luca M, Calamandrei G (2004) Cognitive and neurological deficits induced by early and prolonged basal forebrain cholinergic hypofunction in rats. Exp Neurol 189(1):162-172. doi: 10.1016/j.expneurol.2004.05.025

Summary: A distinctive feature of Alzheimer’s disease is the loss of cholinergic neurons in the basal forebrain (BF). The authors investigated long-term effects of BF cholinergic lesions on several parameters. Administration of 0.21 µg of 192-Saporin (Cat. #IT-01) to the third ventricle of 7 day-old rats was followed by an evaluation of protein levels and cortical EEG patterns at 6 months of age. The findings indicate that permanent neonatal BF cholinergic damage may provide a model for abnormal adult cholinergic function.

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

Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004) Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305-3316. doi: 10.1111/j.0953-816X.2004.03439.x

Summary: In Alzheimer’s disease basal cholinergic degeneration is accompanied by glial activation and the release of pro-inflammatory cytokines. To investigate whether neural events other than degeneration can cause effects of Alzheimer’s disease, the authors treated mice with minocycline after lesioning the basal forebrain with 3.6 µg of mu p75-SAP (Cat. #IT-16). Administration of minocycline reduced the loss of cholinergic neurons, reduced glial response to the lesion, and lessened the cognitive impairment due to mu p75-SAP lesions.

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Kolasa K, Harrell LE (2003) Combined lesions of central cholinergic and noradrenergic denervation in the rat using 192 IgG-saporin and DSP-4 as an animal model of Alzheimer’s disease. Neuroscience 2003 Abstracts 842.6. Society for Neuroscience, New Orleans, LA.

Summary: To better model the consequences of persistent cholinergic hypofunction observed in Alzheimer’s disease, medial septum (MS) lesions were made by using specific cholinotoxin 192-IgG saporin. In this study the effect of simultaneous hippocampal cholinergic denervation, induced by intraseptal injection of 192-IgG saporin, and central noradrenergic denervation, induced by systemic injection of DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) was examined in the rat dorsal hippocampus. DSP-4, an adrenergic neurotoxin selective for locus coeruleus innervated brain regions, induced a decrease in norepinephrine (NE) concentration in hippocampus. MS lesions resulted not only in selective cholinergic denervation of hippocampus (CD; superior cervical ganglion removed to prevent ingrowth of peripheral NE fibers), but also ingrowth of NE fibers into the hippocampus (HI; superior cervical ganglion left intact). MS lesions also resulted in a significant loss of choline-acetyltransferase activity in HI and CD groups, and an increase in NE in the HI group. In the HI group, but not in CD or control groups, visualization of hippocampus revealed a dense NE innervation with fine NE fibers with varicosities. Combination of MS lesion and DSP-4 treatment resulted in a reduction of NE concentration in HI group, with concomitant decrease in visualization of NE fibers. Those that remained were thick with sparse varicosities, possibly derived from peripheral sympathetic ingrowth. Elevated NE concentration and NE fiber number following specific cholinergic lesions might reflect compensatory sprouting of both central and peripheral adrenergic fibers into the hippocampus. Thus, noradrenergic sprouting in response to cholinergic denervation of hippocampus might be a valuable model for studying mechanisms as well as the consequences of neuronal plasticity in the mature CNS.

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

Dudkin KN, Chueva IV, Makarov FN, Beach TG, Roher AE (2003) Impairments of working memory processes on a model of Alzheimer’s disease in monkeys. Neuroscience 2003 Abstracts 626.8. Society for Neuroscience, New Orleans, LA.

Summary: We have investigated the characteristics of visual working memory in a delayed-discrimination task in a model of Alzheimer’s disease (AD) in rhesus monkeys. Three animals received unilateral stereotaxic intracerebroventricular injection of the nucleus basalis of Meynert and three monkeys received sterile saline injections and thus served as controls. The lesioning agent consisted of a ribosomal toxin, saporin, conjugated to monoclonal antibodies against (the nbM lesion) the p75 neurotrophin receptor (p75NTR), which is expressed almost exclusively on cholinergic neurons of the nbM. The rationale for the model is the same as for a rabbit model of AD (Roher et al, Ann. NY Acad Sci. 2000). The monkeys were trained to discriminate stimuli with different types of visual information (spatial frequency gratings, color, spatial choice, spatial relationships between components of objects). The data obtained demonstrate that the nbM lesioning agent had a weak effect on visual differentiation without delay (long-term memory), but significantly decreased the duration of information storage (by a factor of 2 – 3) in working memory later two months after injection. These changes depended on temporal stage after injection and stimulus properties, and were accompanied by increase of motor reaction time and of refusal of task decision. In monkeys that were sham injected, there were no alterations in working memory characteristics. The results suggest that considerable worsening of the working memory characteristics for monkeys after lesion of the nbM reflects the formation of an AD model in these monkeys. The principles of functional organization of working memory and role of pathology of the cortical mechanisms in an impairment of memory characteristics are discussed.

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