Age‐related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild‐type mice

Minkeviciene, Rimante; Ihalainen, Jouni; Malm, Tarja; Matilainen, Olli; Keksa-Goldsteine, Velta; Goldsteins, Gundars; Iivonen, H.; Leguit, N.; Glennon, Jeffrey; Koistinaho, Jari; Banerjee, Pradeep; Tanila, Heikki

doi:10.1111/j.1471-4159.2007.05147.x

Cited by 172 publications

(135 citation statements)

References 34 publications

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“…Both mouse strains had similar responses for glutamate levels when expressed as relative changes of basal values (Fig. 4), although the lower glutamate levels were preserved in transgenic mice when absolute changes of glutamate were graphed (data not shown); thus, our results are in agreement with reduced glutamate release in aged amyloid-bearing mice (Minkeviciene et al, 2008).…”

Section: Downloaded Fromsupporting

confidence: 67%

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 Fromsupporting

confidence: 67%

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

Hartmann¹,

Kiewert²,

Klein³

2009

J Pharmacol Exp Ther

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“…Intriguingly, all reported mouse lines showing epilepsy-associated morphological changes and lowered seizure thresholds had APP mutations favoring the formation of the more easily aggregating A␤1-42 form (Palop et al, 2007). Similarly, the combination of PS1dE9 with APPswe mutation strongly shifts the gamma-cleavage of A␤ toward A␤1-42 (Jankowsky et al, 2004;Minkeviciene et al, 2008). However, because it is well established that APP-induced lethality is highly dependent on the genetic background of mice (Carlson et al, 1997), we cannot fully exclude the possibility that sensitization of neuronal networks to overexcitation by A␤ is not enough to induce generalized seizures without another sensitizing factor such as the PS1 mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Although this line was originally maintained on a hybrid background, mice at the University of Kuopio were backcrossed for nine generations to C57BL/6J mice. Notably, the time course of A␤ pathology is similar in the mouse line kept on a C57BL/ 6J ϫ C3H hybrid background (Garcia-Alloza et al, 2006) as our backcrossed C57BL/6J line (Shemer et al, 2006;Minkeviciene et al, 2008). Throughout the experiments, animals were housed individually in cages in a controlled environment (temperature, 21 Ϯ 1°C; humidity, 50 Ϯ 10%; light period, 7:00 A.M. to 7:00 P.M.) and had ad libitum access to food and water.…”

Section: Animalsmentioning

confidence: 97%

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Minkeviciene¹,

Rheims²,

Dobszay³

et al. 2009

J. Neurosci.

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544

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Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid ␤ (A␤) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of A␤1-42 or A␤25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied A␤ (proto-)fibrils. Overall, these data identify fibrillar A␤ as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.

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“…APP/PS1 transgenic mice expressing mutant human APP and PS1 genes are a useful research tool to study Aβ-related pathogenesis. There are several studies characterizing cognitive as well as noncognitive abnormality in APP/PS1 mice at 15-24 months of age (Morgan et al 2000;Arendash et al 2001;Sadowski et al 2004;Wilcock et al 2004;Hooijmans et al 2007;Minkeviciene et al 2008;Pistell et al 2008;Mei et al 2010;Ke et al 2011;Gengler et al 2012;Manczak and Reddy 2012;Wang et al 2012;Duffy and Hölscher 2013;Do et al 2014;Huang et al 2015;Janus et al 2015;Sahlholm et al 2015;Yousefi et al 2015) (A detailed summary is available in Table 2). However, the majority of experiments utilize young or adult APP/PS1 mice, which does not replicate typical hallmarks of AD, such as severe hippocampal atrophy and extensive neuronal loss (Bales 2012;Bilkei-Gorzo 2014).…”

Section: Discussionmentioning

confidence: 99%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Age‐related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild‐type mice

Cited by 172 publications

References 34 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

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

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Age‐related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild‐type mice

Cited by 172 publications

References 34 publications

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

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

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

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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