Early changes in Aβ levels in the brain of APPswe transgenic mice—Implication on synaptic density, α7 neuronal nicotinic acetylcholine- and N-methyl-d-aspartate receptor levels

Unger, Christina; Hedberg, Monika M.; Mustafiz, Tamanna; Svedberg, Marie; Nordberg, Agneta

doi:10.1016/j.mcn.2005.07.012

Cited by 15 publications

(22 citation statements)

References 51 publications

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“…Analysis of the synaptic vesicle membrane protein synaptophysin in the present study revealed a 5-fold decrease in the cortical levels in APPswe transgenic mice compared with the nontransgenic controls, which is in agreement with earlier observations in young APPswe transgenic mice (Unger et al, 2005a). The finding that treatment with galantamine and nicotine both caused a 2-fold increase in synaptophysin levels in the APPswe transgenic mice may suggest a neurotrophic effect by influencing the possible interaction between A␤ and the ␣7 nAChRs.…”

Section: Discussionsupporting

confidence: 92%

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Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Unger

Svedberg²,

Yu³

et al. 2005

J Pharmacol Exp Ther

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An increasing number of studies suggest that the present clinical therapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The aim of this study was to investigate the effect of the cholinesterase inhibitor galantamine and the N-methyl-D-aspartate (NMDA) antagonist memantine in comparison to nicotine on the neuropathology of Tg2576 transgenic mice (APPswe). Nontransgenic and APPswe mice at 10 months of age were treated subcutaneously with saline, memantine, galantamine, or nicotine for 10 days. Nicotine reduced the guanidinium-soluble amyloid-␤ peptide (A␤) levels by 46 to 66%, whereas the intracellular A␤ levels remained unchanged. Treatment with nicotine also resulted in less glial fibrillary acidic protein immunoreactive astrocytes around the plaques, increased levels of synaptophysin, and increased number of ␣7 nicotinic acetylcholine receptors (nAChRs) in the cortex of APPswe transgenic mice. Galantamine treatment caused an increase in the cortical levels of synaptophysin in the APPswe mice. Memantine treatment reduced the total cortical levels of membrane-bound amyloid precursor protein (45-55%) in both transgenic and nontransgenic mice, which eventually may decrease the level of A␤. In conclusion, galantamine, memantine, and nicotine have different interactions with A␤ processes, ␣7 nAChRs, and NMDA receptors in APPswe mice. These different effects might have therapeutic relevance, and this knowledge might be applicable to the development of new effective therapeutic strategies for AD.

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Section: Discussionsupporting

confidence: 92%

“…Synaptophysin was quantified by immunoblotting as previously described (Unger et al, 2005a). Briefly, 4 to 20% gradient minigels were run at 100-mV constant voltages at room temperature for 60 to 70 min.…”

Section: Western Blotmentioning

confidence: 99%

Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Unger

Svedberg²,

Yu³

et al. 2005

J Pharmacol Exp Ther

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“…The study of proteins and receptors at synaptic sites has provided valuable information about molecular mechanisms underlying neuronal activity Kennedy et al, 1983) as well as the pathogenesis of diseases (Unger et al, 2005) and aging (Helfert et al, 2003). The identification of these proteins at synaptic sites provides valuable information to how the synapses function during synaptic transmission Cohen et al, 1977;Kennedy, 1997;Kennedy et al, 1983;Marrs et al, 2001;Suzuki et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Rapid isolation of synaptoneurosomes and postsynaptic densities from adult mouse hippocampus

Villasana

Klann

Tejada‐Simon

2006

Journal of Neuroscience Methods

108

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Previous postsynaptic density (PSD) isolation methodologies have utilized either whole brain or discrete brain regions of relatively large mammals such as dogs and rats. The present report details a simple and highly effective procedure for the rapid isolation of PSDs from small amounts of adult mouse hippocampus that has several advantages. First, by substituting synaptoneurosomes for synaptosomes as starting material, we have decreased the steps, time, and amount of tissue required to isolate PSDs. Second, by modifying critical steps in the synaptic isolation protocols we were able to isolate PSDs from less than 200 mg of mouse hippocampi in 3 h. Electron micrographs of isolated synaptoneurosomes showed presynaptic vesicles and densely stained membranes representing PSDs. Morphological examination of these PSDs by electron microscopy revealed a preparation that seems to be quite pure, with little or no membrane contamination. A comparison by Western blot analysis of synaptoneurosome and PSD fractions suggests that this technique yields a purified sample. Moreover, two different protocols using swing and fixed bucket rotors were used for this small-scale PSD isolation and both resulted in a very pure partition, supporting the idea that this procedure is reliable and consistent.

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“…Of note however, cholinergic neurons are also integral in the development of amyloid-based pathology Francis et al, 1999;Tran et al, 2002) as they can regulate APP processing and, in turn, A can decrease ACh synthesis and release (Heinitz et al, 2006;Hoshi et al, 1996Hoshi et al, , 1997Kar et al, 1996Kar et al, , 1998Pederson et al, 1996;Pederson & Blusztajn, 1997;Satoh et al, 2001). The stimulation of either nicotinic or muscarinic ACh receptors on cholinoreceptive neurons can promote non-amyloidogenic APP cleavage, thereby potentially decreasing the production of toxic A (Isacson et al, 2002;Seo et al, 2001; www.intechopen.com al., 2002; Unger et al, 2005;Verhoeff, 2005). Thus, the activation of either 7-or 42-nicotinic receptors (Lahiri et al, 2002;Shimohama & Kihara, 2001;Zamani & Allen, 2001) can decrease A toxicity by protecting neurons through activation of PI3-kinase and increasing levels of Bcl-2 and Bcl-x50.…”

Section: Cholinergic Neurons Have a Role In Regulation Of App Metabolismmentioning

confidence: 99%

“…Thus, under conditions of oxidative-nitrosative stress, this effect of reduced synaptic efficacy associated with increasing oligomeric A could further negatively impact CHT protein levels at the plasma membrane. This in turn would lead to diminished cholinergic signalling, a process found to be crucial in maintaining the cholinergic phenotype and regulating APP metabolism (Isacson et al, 2002;Seo et al, 2001;Tran et al, 2002;Unger et al, 2005;Verhoeff, 2005).…”

Section: Subcellular Trafficking Of Cht Proteins An Important Mode Omentioning

confidence: 99%

Impact of Oxidative - Nitrosative Stress on Cholinergic Presynaptic Function

Black¹,

Rylett²

2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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Early changes in Aβ levels in the brain of APPswe transgenic mice—Implication on synaptic density, α7 neuronal nicotinic acetylcholine- and N-methyl-d-aspartate receptor levels

Cited by 15 publications

References 51 publications

Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Rapid isolation of synaptoneurosomes and postsynaptic densities from adult mouse hippocampus

Impact of Oxidative - Nitrosative Stress on Cholinergic Presynaptic Function

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