scholarly journals Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive and Electrophysiological Impairments in Tg2576 APP Transgenic Mice

2021 ◽  
Vol 79 (4) ◽  
pp. 1813-1829
Author(s):  
Madhumathi Gnanaprakash ◽  
Agnieszka Staniszewski ◽  
Hong Zhang ◽  
Rose Pitstick ◽  
Michael P. Kavanaugh ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Protein Phosphatase ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Molecular Pathogenesis ◽  
Short Term ◽  
Tg2576 Mice ◽  
Pathogenic Effects

Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ.

scholarly journals In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid β-peptide of APP

2010 ◽  
Vol 48 (1) ◽  
pp. 136-144 ◽  
Author(s):  
D. Allan Butterfield ◽  
Veronica Galvan ◽  
Miranda Bader Lange ◽  
Huidong Tang ◽  
Renã A. Sowell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Methionine 35

scholarly journals N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

2019 ◽  
Vol 116 (47) ◽  
pp. 23426-23436 ◽  
Author(s):  
Min Hee Park ◽  
Misun Lee ◽  
Geewoo Nam ◽  
Mingeun Kim ◽  
Juhye Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Causative Factor ◽  
Central Feature ◽  
Microglial Phagocytosis ◽  
Cognitive Defects

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Modeling the short-term dynamics of in vivo excitatory spike transmission

2018 ◽  
Author(s):  
Abed Ghanbari ◽  
Naixin Ren ◽  
Christian Keine ◽  
Carl Stoelzel ◽  
Bernhard Englitz ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Large Scale ◽  
Auditory Brainstem ◽  
Postsynaptic Neuron ◽  
Intracellular Recordings ◽  
Short Term ◽  
Functional Connection ◽  
Synaptic Dynamics ◽  
Synaptic Effects

AbstractInformation transmission in neural networks is influenced by both short-term synaptic plasticity (STP) as well as non-synaptic factors, such as after-hyperpolarization currents and changes in excitability. Although these effects have been widely characterized in vitro using intracellular recordings, how they interact in vivo is unclear. Here we develop a statistical model of the short-term dynamics of spike transmission that aims to disentangle the contributions of synaptic and non-synaptic effects based only on observed pre- and postsynaptic spiking. The model includes a dynamic functional connection with short-term plasticity as well as effects due to the recent history of postsynaptic spiking and slow changes in postsynaptic excitability. Using paired spike recordings, we find that the model accurately describes the short-term dynamics of in vivo spike transmission at a diverse set of identified and putative excitatory synapses, including a thalamothalamic connection in mouse, a thalamocortical connection in a female rabbit, and an auditory brainstem synapse in a female gerbil. We illustrate the utility of this modeling approach by showing how the spike transmission patterns captured by the model may be sufficient to account for stimulus-dependent differences in spike transmission in the auditory brainstem (endbulb of Held). Finally, we apply this model to large-scale multi-electrode recordings to illustrate how such an approach has the potential to reveal cell-type specific differences in spike transmission in vivo. Although short-term synaptic plasticity parameters estimated from ongoing pre- and postsynaptic spiking are highly uncertain, our results are partially consistent with previous intracellular observations in these synapses.Significance StatementAlthough synaptic dynamics have been extensively studied and modeled using intracellular recordings of post-synaptic currents and potentials, inferring synaptic effects from extracellular spiking is challenging. Whether or not a synaptic current contributes to postsynaptic spiking depends not only on the amplitude of the current, but also on many other factors, including the activity of other, typically unobserved, synapses, the overall excitability of the postsynaptic neuron, and how recently the postsynaptic neuron has spiked. Here we developed a model that, using only observations of pre- and postsynaptic spiking, aims to describe the dynamics of in vivo spike transmission by modeling both short-term synaptic plasticity and non-synaptic effects. This approach may provide a novel description of fast, structured changes in spike transmission.

scholarly journals Altered Amyloid-β Metabolism and Deposition in Genomic-based β-Secretase Transgenic Mice

2004 ◽  
Vol 279 (50) ◽  
pp. 52535-52542 ◽  
Author(s):  
Matthew J. Chiocco ◽  
Laura Shapiro Kulnane ◽  
Linda Younkin ◽  
Steve Younkin ◽  
Geneviève Evin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Transgenic Animals ◽  
Brain Regions ◽  
Primary Component ◽  
App Processing ◽  
Bace1 Expression ◽  
First Time

Amyloid-β (Aβ) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by β-secretase followed by γ-secretase cleavage. Identification of the primary β-secretase gene,BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Aβ metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating β-secretase expression and activity alters APP processing and Aβ metabolismin vivo. Genomic-basedBACE1transgenic mice were generated that overexpress humanBACE1mRNA and protein. The highest expressingBACE1transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing bothBACE1andAPPshow specific alterations in APP processing and age-dependent Aβ deposition. We observed elevated levels of Aβ isoforms as well as significant increases of Aβ deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for β-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation ofBACE1activity may play a significant role in AD pathogenesisin vivo.

Short-term synaptic plasticity in the rat geniculo-cortical pathway during development in vivo

2006 ◽  
Vol 398 (1-2) ◽  
pp. 73-77 ◽  
Author(s):  
Fan Jia ◽  
Haiyang Wei ◽  
Xiangrui Li ◽  
Xiaoqiao Xie ◽  
Yifeng Zhou
Keyword(s):  
Synaptic Plasticity ◽  
Short Term

YAC128 Huntington׳s disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease

2014 ◽  
Vol 1581 ◽  
pp. 117-128 ◽  
Author(s):  
Mohamed Ghilan ◽  
Crystal A. Bostrom ◽  
Brett N. Hryciw ◽  
Jessica M. Simpson ◽  
Brian R. Christie ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Short Term ◽  
Hippocampal Synaptic Plasticity

scholarly journals A Role for Short-Term Synaptic Facilitation and Depression in the Processing of Intensity Information in the Auditory Brain Stem

2007 ◽  
Vol 97 (4) ◽  
pp. 2863-2874 ◽  
Author(s):  
K. M. MacLeod ◽  
T. K. Horiuchi ◽  
C. E. Carr
Keyword(s):  
Synaptic Plasticity ◽  
Brain Stem ◽  
Time Constant ◽  
Cochlear Nucleus ◽  
Auditory Nerve ◽  
Brain Slices ◽  
Fast Time ◽  
Short Term ◽  
Intensity Information

The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird's cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of ∼40 ms), and a two-step recovery from depression (with one slow time constant of ∼8 s, and one fast time constant of ∼20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.

Unsupervised Formation of Vocalization-Sensitive Neurons: A Cortical Model Based on Short-Term and Homeostatic Plasticity

2012 ◽  
Vol 24 (10) ◽  
pp. 2579-2603 ◽  
Author(s):  
Tyler P. Lee ◽  
Dean V. Buonomano
Keyword(s):  
Synaptic Plasticity ◽  
Direction Selectivity ◽  
Homeostatic Plasticity ◽  
Cortical Model ◽  
Short Term ◽  
Temporal Asymmetry ◽  
Complex Stimuli ◽  
Spike Patterns

The discrimination of complex auditory stimuli relies on the spatiotemporal structure of spike patterns arriving in the cortex. While recordings from auditory areas reveal that many neurons are highly selective to specific spatiotemporal stimuli, the mechanisms underlying this selectivity are unknown. Using computer simulations, we show that selectivity can emerge in neurons in an entirely unsupervised manner. The model is based on recurrently connected spiking neurons and synapses that exhibit short-term synaptic plasticity. During a developmental stage, spoken digits were presented to the network; the only type of long-term plasticity present was a form of homeostatic synaptic plasticity. From an initially unresponsive state, training generated a high percentage of neurons that responded selectively to individual digits. Furthermore, units within the network exhibited a cardinal feature of vocalization-sensitive neurons in vivo: differential responses between forward and reverse stimulus presentations. Direction selectivity deteriorated significantly, however, if short-term synaptic plasticity was removed. These results establish that a simple form of homeostatic plasticity is capable of guiding recurrent networks into regimes in which complex stimuli can be discriminated. In addition, one computational function of short-term synaptic plasticity may be to provide an inherent temporal asymmetry, thus contributing to the characteristic forward-reverse selectivity.

Sign in / Sign up

Export Citation Format

Share Document