A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

Identifying which among several in cellulo pharmacological activities is necessary for the proper in vivo activity is essential for further drug development against Alzheimer’s disease pathophysiological processes. An in-depth structure–activity relationship–based study has been carried out, and two molecules, named MAGS02-14 and PEL24-199, that share a ß-secretase modulatory effect associated or not to a lysosomotropic activity in cellulo have been identified. In terms of chemical formulas, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. The study aimed to elucidate the in vivo pharmacological effects of lysosomotropic and/or the ß-secretase modulatory activity in a tau pathology mouse model. To address this question, the THY-Tau22 transgenic model of tauopathy was treated with both compounds for 6 weeks in a curative paradigm. Short-term memory, tau burden, and inflammatory processes were analyzed using orthogonal methods, and PEL24-199, but not MAGS02-14, was shown to restore the short-term memory and reduce the neurofibrillary degenerating process. These effects were associated with a reduced phosphorylation of tau, an increased phosphatase expression, and decreased astrogliosis. Our results, therefore, suggest that the lysosomotropic activity may be nonessential for the effect on tau pathology.

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A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration

10.1101/2021.04.02.438175 ◽

2021 ◽

Author(s):

Marie Tautou ◽

Sabiha Eddarkaoui ◽

Florian Descamps ◽

Paul-Emmanuel Larchanche ◽

Melanie Dumoulin ◽

...

Keyword(s):

Nitrogen Atom ◽

Mouse Model ◽

Short Term Memory ◽

Tau Pathology ◽

Short Term ◽

Term Memory ◽

Transgenic Model ◽

Structure Activity ◽

Inflammatory Processes

A structure-activity relationship has enabled us to identify two molecules, MAGS02-14 and PEL24-199, sharing a β-secretase modulatory effect but having or not a lysosomotropic activity, respectively. More importantly, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. However, which of the lysosomotropic and/or β-secretase modulating activities is necessary for the pharmacological effect in vivo remains ill-defined. To address this question, the THY-Tau22 transgenic model of NFD was treated for 6 weeks in a curative paradigm and short-term memory, Tau burden, and inflammatory processes were studied. PEL24-199, possessing only the β-secretase modulatory activity, was shown to restore the short-term memory and to reduce NFD. This effect was associated with reduced phosphorylation of Tau, increased phosphatase expression, and a decrease of astrogliosis. Our results, therefore, suggest that the lysosomotropic activity may be dispensable for the effect on both Aβ and Tau pathologies.

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Tyr-Trp administration facilitates brain norepinephrine metabolism and ameliorates a short-term memory deficit in a mouse model of Alzheimer’s disease

PLoS ONE ◽

10.1371/journal.pone.0232233 ◽

2020 ◽

Vol 15 (5) ◽

pp. e0232233 ◽

Cited By ~ 1

Author(s):

Takashi Ichinose ◽

Hiroyasu Murasawa ◽

Tomoko Ishijima ◽

Shinji Okada ◽

Keiko Abe ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Short Term Memory ◽

Memory Deficit ◽

Short Term ◽

Term Memory ◽

Brain Norepinephrine ◽

Model Of Alzheimer’S Disease ◽

Norepinephrine Metabolism

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Inhaled nitric oxide improves short term memory and reduces the inflammatory reaction in a mouse model of mild traumatic brain injury

Brain Research ◽

10.1016/j.brainres.2013.05.032 ◽

2013 ◽

Vol 1522 ◽

pp. 67-75 ◽

Cited By ~ 15

Author(s):

Ping Liu ◽

Yong-sheng Li ◽

David Quartermain ◽

Allal Boutajangout ◽

Yong ji

Keyword(s):

Nitric Oxide ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mouse Model ◽

Mild Traumatic Brain Injury ◽

Inflammatory Reaction ◽

Short Term Memory ◽

Inhaled Nitric Oxide ◽

Short Term ◽

Term Memory

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Restitution and adaptation measurements for the estimate of short-term cardiac action potential memory: comparison of five human ventricular models

EP Europace ◽

10.1093/europace/euz205 ◽

2019 ◽

Vol 21 (10) ◽

pp. 1594-1602

Author(s):

Massimiliano Zaniboni ◽

Francesca Cacciani

Keyword(s):

Steady State ◽

Action Potential ◽

Short Term Memory ◽

Computational Study ◽

Numerical Models ◽

Cardiac Action Potential ◽

Short Term ◽

Term Memory ◽

Cardiac Action

Abstract Aims This computational study refines our recently published pacing protocol to measure short-term memory (STM) of cardiac action potential (AP), and apply it to five numerical models of human ventricular AP. Methods and results Several formulations of electrical restitution (ER) have been provided over the years, including standard, beat-to-beat, dynamic, steady-state, which make it difficult to compare results from different studies. We discuss here the notion of dynamic ER (dER) by relating it to its steady-state counterpart, and propose a pacing protocol based on dER to measure STM under periodically varying pacing cycle length (CL). Under high and highly variable-pacing rate, all models develop STM, which can be measured over the entire sequence by means of dER. Short-term memory can also be measured on a beat-to-beat basis by estimating action potential duration (APD) adaptation after clamping CL constant. We visualize STM as a phase shift between action potential (AP) parameters over consecutive cycles of CL oscillations, and show that delay between CL and APD oscillation is nearly constant (around 92 ms) in the five models, despite variability in their intrinsic AP properties. Conclusion dER, as we define it and together with other approaches described in the study, provides an univocal way to measure STM under extreme cardiac pacing conditions. Given the relevance of AP memory for repolarization dynamics and stability, STM should be considered, among other usual biomarkers, to validate and tune cardiac AP models. The possibility of extending the method to in vivo cellular and whole organ models can also be profitably explored.

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Enhancement of Short-Term Memory by Methyl-6-(Phenylethynyl)-Pyridine in the BTBR T+tf/J Mouse Model of Autism Spectrum Disorder

Endocrinology and Metabolism ◽

10.3803/enm.2015.30.1.98 ◽

2015 ◽

Vol 30 (1) ◽

pp. 98 ◽

Cited By ~ 8

Author(s):

Haijie Yang ◽

Sung-Oh Huh ◽

Jae Seung Hong

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Short Term Memory ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Short Term ◽

Term Memory

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Deep brain stimulation facilitates memory in a model of Alzheimer’s disease

Translational Neuroscience ◽

10.2478/v10134-010-0026-7 ◽

2010 ◽

Vol 1 (2) ◽

Cited By ~ 1

Author(s):

Isabel Arrieta-Cruz ◽

Constantine Pavlides ◽

Giulio Pasinetti

Keyword(s):

Short Term Memory ◽

Hippocampal Slices ◽

In Vivo Studies ◽

Short Term ◽

Term Memory ◽

Ca1 Region ◽

Secretase Activity ◽

Tgcrnd8 Mice ◽

Deep Brain

AbstractBased on evidence suggesting that deep brain stimulation (DBS) may promote certain cognitive processes, we have been interested in developing DBS as a means of mitigating memory and learning impairments in Alzheimer’s disease (AD). In this study we used an animal model of AD (TgCRND8 mice) to determine the effects of high-frequency stimulation (HFS) on non-amyloidogenic α-secretase activity and DBS in short-term memory. We tested our hypothesis using hippocampal slices (in vitro studies) from TgCRND8 mice to evaluate whether HFS increases α-secretase activity (non-amyloidogenic pathway) in the CA1 region. In a second set of experiments, we performed in vivo studies to evaluate whether DBS in midline thalamic region re-establishes hippocampal dependent short-term memory in TgCRND8 mice. The results showed that application of HFS to isolated hippocampal slices significantly increased synaptic plasticity in the CA1 region and promoted a 2-fold increase of non-amyloidogenic α-secretase activity, in comparison to low frequency stimulated controls from TgCRND8 mice. In the in vivo studies, DBS treatment facilitated acquisition memory in TgCRND8 mice, in comparison to their own baseline before treatment. These results provide evidence that DBS could enhance short-term memory in a mouse model of AD by increasing synaptic transmission and α-secretase activity in the CA1 region of hippocampus.

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