Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain

Vogt, Daniel; Thomas, Dustin; Galván, Verónica; Bredesen, Dale E.; Lamb, Bruce T.; Pimplikar, Sanjay W.

doi:10.1016/j.neurobiolaging.2009.09.002

Cited by 96 publications

(86 citation statements)

References 18 publications

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“…This is in accordance with earlier findings of others who demonstrated that seizure susceptibility is increased in AD model mice (Westmark et al 2008;Vogt et al 2009), and heat shock proteins can moderate chemically induced seizures (Akbar et al 2003;Ekimova et al 2010). LTP, a cellular correlate of learning and memory (Bliss and Colingridge 1993), was also investigated on hippocampal slices.…”

Section: Discussionsupporting

confidence: 89%

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

Tóth

Szegedi

Varga

et al. 2013

Cell Stress and Chaperones

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Hsp27 belongs to the small heat shock protein family, which are ATP-independent chaperones. The most important function of Hsp27 is based on its ability to bind non-native proteins and inhibit the aggregation of incorrectly folded proteins maintaining them in a refolding-competent state. Additionally, it has anti-apoptotic and antioxidant activities. To study the effect of Hsp27 on memory and synaptic functions, amyloid-β (Aβ) accumulation, and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS1dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using different behavioral tests, we found that spatial learning was impaired in AD model mice and was rescued by Hsp27 overexpression. Electrophysiological recordings have revealed that excitability of neurons was significantly increased, and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS1dE9/Hsp27 animals compared to AD model mice. These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD.

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Section: Discussionsupporting

confidence: 89%

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

Tóth

Szegedi

Varga

et al. 2013

Cell Stress and Chaperones

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“…These alterations include reductions in calbindin and increases in neuropeptide Y (NPY; Palop et al 2003;Palop et al 2007). Video electroencephalogram (EEG) telemetry recordings in freely behaving hAPP mice have detected widespread cortical and hippocampal epileptiform activity Minkeviciene et al 2009;Vogt et al 2009;Roberson et al 2011). Some of these EEG studies also documented intermittent, nonconvulsive seizures that were difficult or impossible to detect by visual observation.…”

Section: Disruption Of Cognitive Functions: From Synapses To Neural Nmentioning

confidence: 99%

Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction

Mucke

Selkoe

2012

Cold Spring Harbor Perspectives in Medicine

884

734

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Evidence for an ever-expanding variety of molecular mediators of amyloid b-protein neurotoxicity (membrane lipids, receptor proteins, channel proteins, second messengers and related signaling cascades, cytoskeletal proteins, inflammatory mediators, etc.) has led to the notion that the binding of hydrophobic Ab assemblies to cellular membranes triggers multiple effects affecting diverse pathways. It appears unlikely that there are only one or two cognate receptors for neurotoxic forms of Ab and also that there are just one or two assembly forms of the peptide that induce neuronal dysfunction. Rather, various soluble (diffusible) oligomers of Ab that may be in dynamic equilibrium with insoluble, fibrillar deposits (amyloid plaques) and that can bind to different components of neuronal and non-neuronal plasma membranes appear to induce complex patterns of synaptic dysfunction and network disorganization that underlie the intermittent but gradually progressive cognitive manifestations of the clinical disorder. Modern analyses of this problem utilize electrophysiology coupled with synaptic biochemistry and behavioral phenotyping of animal models to elucidate the affected circuits and assess the effects of potential therapeutic interventions.

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“…Subsequent neurodegeneration and working memory deficits were also observed in these transgenic mice [96]. In other experiments, similar transgenic mice exhibited abnormal spiking events in their electroencephalograms and susceptibility to kainic acid-induced seizures independent of Aβ [97]. Furthermore, the function of c-Abl kinase in the transcriptional regulation of AICD was reported and c-Abl was shown to modulate AICD-dependent cellular responses, transcriptional induction, as well as apoptotic responses [98].…”

Section: Signaling Functions Of Aicdmentioning

confidence: 74%