Impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mice

Machová, Eva; Jakubík, Ján; Michal, Pavel; Oksman, Mari; Iivonen, H.; Tanila, Heikki; Doležal, Vladimı́r

doi:10.1016/j.neurobiolaging.2006.10.029

Cited by 46 publications

(40 citation statements)

References 69 publications

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“…Therefore, this study indicates that presynaptic cholinergic function is largely unchanged in amyloid-bearing mice. It should be noted that our results do not exclude potential interactions of amyloid peptides with postsynaptic cholinergic signaling; for example, A␤ peptides interfere with both nicotinic (Dineley et al, 2001;Abbott et al, 2008) and muscarinic signaling (Goto et al, 2008;Machová et al, 2008), but these interactions were not addressed in the present study. It is noteworthy that basal glutamate levels were decreased in APP SWE /PS1dE9 mice, although the responses to stimulation were preserved.…”

Section: Downloaded Frommentioning

confidence: 66%

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Hartmann¹,

Kiewert²,

Klein³

2009

J Pharmacol Exp Ther

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Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, synaptic loss and central cholinergic dysfunction, dysfunction of energy metabolism, and dementia; however, the interactions between these hallmarks remain poorly defined. We studied a well characterized mouse model of amyloid deposition, the doubly transgenic APP SWE ϫPSEN1dE9 mouse. At 10 to 14 months of age, these mice had high levels of amyloid peptides (6.6 g/g wet weight) and widespread amyloid plaques. Extracellular levels of acetylcholine (ACh) were determined by microdialysis in the hippocampus and were comparable with nontransgenic mice from the same colony. In the open field, both mouse strains responded with a 3-fold increase of hippocampal ACh release. Exploratory behavior of the transgenic mice appeared normal. Infusion of scopolamine evoked 5-to 6-fold increases of ACh levels in both mouse strains. High-affinity choline uptake and cholinesterase activities were identical in both mouse lines. Extracellular levels of glucose and glycerol were similar in control and transgenic mice, whereas lactate levels were slightly (p ϭ 0.06) and glutamate levels significantly (p ϭ 0.02) lower in transgenic mice. Exploration caused increases of glucose and lactate, whereas infusion of scopolamine (1 M) increased glucose but not lactate. Glutamate levels were increased by scopolamine, whereas glycerol remained constant under all the conditions. We conclude that amyloid peptide production and plaque deposition causes minor changes in cholinergic function and energy metabolites in transgenic mice in vivo. Amyloid peptide formation and/or deposition may not be sufficient for long-term cholinergic or metabolic dysfunction.Alzheimer's disease (AD) is the most frequent type of dementia in humans and is characterized by cognitive dysfunction and early memory loss (Blennow et al., 2006;Burns and Iliffe, 2009). AD brains display amyloid plaques and neurofibrillary tangles, as well as neuronal degeneration and generalized atrophy. Cholinergic fibers originating in the basal forebrain and innervating hippocampus and cortex seem to degenerate relatively early in the disease, although the clinical evidence is somewhat controversial (Mesulam, 2006;Schliebs and Arendt, 2006). In later stages of the disease, cholinergic dysfunction correlates well with dementia, and current therapies of AD use inhibitors of acetylcholinesterase (AChE) to enhance cholinergic transmission in the brain. Although treatment of AD with AChE inhibitors as a monotherapy has only limited effects, successful treatment of dementia will probably not be possible without correcting the cholinergic deficit. Thus, the understanding of the cholinergic dysfunction and its development remains highly relevant for drug treatment of AD.In clinical studies, AD can be distinguished in early onset disease (familial AD) and late-onset, sporadic disease (Blennow et al., 2006;Burns and Iliffe, 2009). The rare familial AD cases have mutations in genes coding for...

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Section: Downloaded Frommentioning

confidence: 66%

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Hartmann¹,

Kiewert²,

Klein³

2009

J Pharmacol Exp Ther

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“…Additionally, Amigo et al [49] used LZ for estimating the entropy rate of spike trains and underlined that LZ is closely related to such important source properties as entropy and compression ratio, but in contrast to these, it is a property of individual sequences [49] . Previous studies [58][59][60][61][62] in transgenic (Tg) mice models of Alzheimer's Disease (AD) point out the presence of quite a number of beta-amyloid deposit in the hippocampus and other brain areas as well as cholinergic dysfunction and impairment in learning and memory functions. Therefore a vast amount of research has been done to make a comparison between the 7 month-old Tg and WT (wild type) mice in terms of the intracellular pathways that might be switched on/off in the hippocampal areas.…”

Section: Discussionmentioning

confidence: 99%

“…We speculate that the reason for the drastic drop in the complexity of burst-type neural activity of TG mice is the declined cholinergic neurotransmission that has been reported in TG mouse models in several studies. This neurotransmission deterioration was shown to be caused by the formation of amyloid β-peptide deposits [59][60][61] . The even larger decrease in complexity values that we observed in our data for the older group matches with results that indicate the deterioration to be age-dependent [59,60] .…”

Section: Discussionmentioning

confidence: 99%

“…This neurotransmission deterioration was shown to be caused by the formation of amyloid β-peptide deposits [59][60][61] . The even larger decrease in complexity values that we observed in our data for the older group matches with results that indicate the deterioration to be age-dependent [59,60] . Therefore, our analysis indicates that the LZ based complexity estimator is a useful tool for the characterization of the dynamical changes in hippocampal oscillations.…”

Section: Discussionmentioning

confidence: 99%

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Nonlinear dynamical analysis of carbachol induced hippocampal oscillations in mice

et al. 2009

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Aim: Hippocampal neuronal network and synaptic impairment underlie learning and memory deficit in Alzheimer's disease (AD) patients and animal models. In this paper, we analyzed the dynamics and complexity of hippocampal neuronal network synchronization induced by acute exposure to carbachol, a nicotinic and muscarinic receptor co-agonist, using the nonlinear dynamical model based on the Lempel-Ziv estimator. We compared the dynamics of hippocampal oscillations between wild-type (WT) and triple-transgenic (3xTg) mice, as an AD animal model. We also compared these dynamic alterations between different age groups (5 and 10 months). We hypothesize that there is an impairment of complexity of CChinduced hippocampal oscillations in 3xTg AD mice compared to WT mice, and that this impairment is age-dependent. Methods: To test this hypothesis, we used electrophysiological recordings (field potential) in hippocampal slices. Results: Acute exposure to 100 µmol/L CCh induced field potential oscillations in hippocampal CA1 region, which exhibited three distinct patterns: (1) continuous neural firing, (2) repeated burst neural firing and (3) the mixed (continuous and burst) pattern in both WT and 3xTg AD mice. Based on Lempel-Ziv estimator, pattern (2) was significantly lower than patterns (1) and (3) in 3xTg AD mice compared to WT mice (P<0.001), and also in 10-month old WT mice compared to those in 5-month old WT mice (P<0.01). Conclusion: These results suggest that the burst pattern (theta oscillation) of hippocampal network is selectively impaired in 3xTg AD mouse model, which may reflect a learning and memory deficit in the AD patients.

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“…Preparation of homogenates and membranes, measurement of total muscarinic receptors and enzyme activities, and muscarinic receptormediated activation of G-proteins were carried out as described previously (Machova et al 2008 S; 500 pM, ARC) binding to membranes (5-15 lg protein). Non-specific binding was determined in the presence of 10 lM unlabeled GTP-cS.…”

Section: Biochemical Determinationsmentioning

confidence: 99%

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

Dolejší

Liraz

Rudajev

et al. 2015

Journal of Neurochemistry

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Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Keywords: acetylcholine release, Alzheimer's disease (AD), apolipoprotein E4 (apoE4), hippocampus. J. Neurochem. (2016) 136, 503-509. Cholinergic impairments are a hallmark of Alzheimer's disease (AD) (Craig et al. 2011). Genetic studies revealed that the allele e4 of apolipoprotein (APOE4 gene, apoE4 protein) is the most prevalent genetic risk factor for AD (Corder et al. 1993;Saunders et al. 1993). ApoE4 in AD and normal subjects is associated with biochemical cholinergic impairments (Reinvang et al. 2013). Furthermore, the response of apoE4-carrying AD patients (Braga et al. 2015) and normal controls (Pomara et al. 2004) to pharmacological cholinergic activation is impaired relative to corresponding subjects who express apolipoprotein E3 (apoE3), the AD benign isoform of this molecule. However, the extent to which apoE4 affects the release of acetylcholine (ACh) has not yet been determined.Transgenic mice have been prepared that express apoE4 or apoE3 under the regulation of either astrocytic or neuronal promoters, in addition to apoE-targeted replacement (TR) mice in which the endogenous mouse apoE was replaced by human apoE4 and apoE3 (Sullivan et al. 2011). Of these mice, the TR apoE mice have become the standard model in the field. Measurement of long-term potentiation (LTP) revealed a lower response in apoE4 TR mice ...

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Impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mice

Cited by 46 publications

References 69 publications

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Nonlinear dynamical analysis of carbachol induced hippocampal oscillations in mice

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

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Impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mice

Cited by 46 publications

References 69 publications

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APPSWE×PSEN1dE9 Mouse Brain

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APPSWE×PSEN1dE9 Mouse Brain

Nonlinear dynamical analysis of carbachol induced hippocampal oscillations in mice

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

Contact Info

Product

Resources

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Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain

Neurotransmitters and Energy Metabolites in Amyloid-Bearing APP_SWE×PSEN1dE9 Mouse Brain