In vivo consequences of M1-receptor activation by talsaclidine

Walland, A; Burkard, St.; Hammer, Rudolf; Tröger, Wolfgang

doi:10.1016/s0024-3205(97)00037-4

Cited by 9 publications

(3 citation statements)

References 6 publications

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“…Secretion of sAPPα was enhanced by electrical stimulation of tissue slices from rat brain, which could be blocked by the sodium‐channel antagonist tetrodotoxin (Nitsch et al, 1993). Selective activation of M1/M3, but not M2/M4‐mAChR increased sAPPα secretion and decreased total β‐amyloid formation both in vitro (Ensinger et al, 1993; Farber et al, 1995; Müller et al, 1997; Walland et al, 1997) and in vivo in patients with Alzheimer's disease (Hock et al, 2003; Nitsch et al, 2002). A similar effect could be achieved by direct activation of protein kinase C (PKC) by phorbol este, indicating that mAChR mediate their effects on APP processing through activation of the phosphatidyl inositol signaling pathway (Hung et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer‐like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein

Liskowsky

Schliebs

2006

Intl J of Devlp Neuroscience

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The molecular mechanisms of the interrelationship between cholinergic neurotransmission, processing of amyloid precursor protein (APP) and beta-amyloid (Abeta) production in vivo are still less understood. To reveal any effect of cholinergic dysfunction on APP processing in vivo, 11-month-old transgenic Tg2576 mice with Abeta plaque pathology received intraperitoneal injections of scopolamine at a daily dosage of 2mg/kg body weight for 14 days in order to suppress cortical cholinergic transmission by chronic inhibition of muscarinic acetylcholine receptors. Scopolamine treatment of transgenic Tg2576 mice resulted in increased levels of fibrillar Abeta(1-40) and Abeta(1-42), while the soluble, SDS-extractable Abeta level remained unchanged as compared to vehicle-injected Tg2576 mice. alpha-Secretase activity determined in cortical tissue from scopolamine-treated Tg2576 mice was lower by about 30% as compared to that assayed in control mice, while beta-secretase activity and BACE1 protein expression appeared unaffected by scopolamine treatment. The amount of sAPPalpha, the product secreted by alpha-secretase-mediated APP cleavage, and the unprocessed APP were assayed in the soluble and membrane fraction, respectively, of cortical tissue preparations from treated and control mice by Western blotting. Using the anti antibody 6E10 which specifically labels human sAPPalpha and full length APP in transgenic Tg2576, an enhanced APP level was detected in the membrane fraction from treated mice as compared to controls, while in the soluble fraction scopolamine treatment did not affect the protein level of sAPPalpha. These data indicate an accumulation of APP in cortical membrane fraction in scopolamine-treated Tg2576 mice presumably due to the decreased level of alpha-secretase-mediated APP cleavage, and further suggest that chronic suppression of cortical muscarinic cholinergic transmission may alter the balance between alpha- and beta-secretory APP processing by favouring the amyloidogenic route.

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Section: Introductionmentioning

confidence: 99%

Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer‐like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein

Liskowsky

Schliebs

2006

Intl J of Devlp Neuroscience

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“…Secretion of sAPPa was enhanced by electrical stimulation of tissue slices from rat brain, which could be blocked by the sodium-channel antagonist tetrodotoxin (27). Selective activation of M1/M3-but not M2/M4-mAChR increased sAPPa secretion and decreased total b-amyloid formation both in vitro (28)(29)(30)(31) and in vivo in patients with Alzheimer's disease (32,33). A similar effect could be achieved by direct activation of protein kinase C (PKC) by phorbol ester indicating that mAChR mediate their effects on APP processing through activation of the phosphatidyl inositol signaling pathway (34).…”

Section: Cholinergic Neurotransmission B-amyloid and App Processing mentioning

confidence: 99%

“…Infusion of b-amyloid (1-42) or (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) into the rat nucleus basalis produced a marked cholinergic cell loss and reduced cortical AChE-positive fibre density that was accompanied by enhanced cortical nitric oxide synthase activity, behavioural dysfunctions and impaired learning and memory (52,53). NMDA receptor antagonists and radical scavenger could protect cholinergic neurons of the basal forebrain against b-amyloid neurotoxicity (54) suggesting that b-amyloid neurotoxicity is mediated via an excitotoxic pathway (55,56).…”

Section: B-amyloid Differentially Affects Cortical Cholinergic Transmmentioning

confidence: 99%

Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease – Interrelationship with β-amyloid, Inflammation and Neurotrophin Signaling

Schliebs

2005

Neurochem Res

154

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Alzheimer's disease, the most common neurodegenerative disorder of senile dementia, is characterized by two major morpho-pathological hallmarks. Deposition of extracellular neuritic, beta-amyloid peptide-containing plaques (senile plaques) in cerebral cortical regions of Alzheimer patients is accompanied by the presence of intracellular neurofibrillary tangles in cerebral pyramidal neurons. Basal forebrain cholinergic dysfunction is also a consistent feature of Alzheimer's disease, which has been suggested to cause, at least partly, the cognitive deficits observed in patients with Alzheimer's disease. Impaired cortical cholinergic neurotransmission may also contribute to beta-amyloid plaque pathology in Alzheimer's disease by affecting expression and processing of the beta-amyloid precursor protein (APP). Vice versa, low level of soluble beta-amyloid has been observed to inhibit cholinergic synaptic function. Deposition of beta-amyloid plaques in Alzheimer's disease is also accompanied by a significant plaque-associated glial up-regulation of interleukin-1, which has been attributed to affect expression and metabolism of APP and to interfere with cholinergic transmission. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic dysfunction, beta-amyloid formation and deposition, as well as local inflammatory upregulation, would allow to derive potential treatment strategies to pharmacologically intervene in the disease-causing signaling cascade.

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Alzheimerʼs Disease

Schliebs

2014

Springer Handbook of Bio-/Neuroinformatics

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In vivo consequences of M1-receptor activation by talsaclidine

Cited by 9 publications

References 6 publications

Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer‐like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein

Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer‐like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein

Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease – Interrelationship with β-amyloid, Inflammation and Neurotrophin Signaling

Alzheimerʼs Disease

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