scholarly journals P3-471: Chronic administration of CHF5074, a novel gamma-secretase modulator, dose-dependently restores object recognition memory in aged Alzheimer's disease transgenic mice

2010 ◽  
Vol 6 ◽  
pp. S591-S592
Author(s):  
Bruno P. Imbimbo ◽  
Luciana Giardino ◽  
Alessandro Giuliani ◽  
Marco Gusciglio ◽  
Luca Lorenzini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Object Recognition ◽  
Recognition Memory ◽  
Transgenic Mice ◽  
Chronic Administration ◽  
Gamma Secretase ◽  
Object Recognition Memory

scholarly journals A Novel Heptapeptide, GPPGPAG Transfers to the Brain, and Ameliorates Memory Dysfunction and Dendritic Atrophy in Alzheimer’s Disease Model Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Chihiro Tohda ◽  
Chisato Kogure ◽  
Kaori Nomoto ◽  
Andreia de Toledo ◽  
Ximeng Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Object Recognition ◽  
Recognition Memory ◽  
Oral Administration ◽  
Cortical Neurons ◽  
Object Recognition Memory ◽  
5Xfad Mice ◽  
Dendritic Atrophy ◽  
The Brain

We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in Alzheimer’s disease models to evaluate its potency as a new anti-Alzheimer’s disease (AD) therapy. The anti-AD effects of GPPGPAG were evaluated in Aβ-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aβ25-35 for 3 days resulted in atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic atrophy of Aβ-treated cortical neurons, but not axonal atrophy. Postsynaptic and presynaptic densities under Aβ1-42 exposure were increased by GPPGPAG post treatment. Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound protein. The protective effect of GPPGPAG on Aβ1-42-induced dendritic atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.

scholarly journals Targeting the RHOA pathway improves learning and memory in Kctd13 and 16p11.2 deletion mouse models

2020 ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann Herault
Keyword(s):  
Object Recognition ◽  
Recognition Memory ◽  
Mouse Models ◽  
Copy Number Variants ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
List Type ◽  
Object Recognition Memory

ABSTRACTGene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models.HIGHLIGHTS- Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2 Del/+ models- Fasudil treatment restores Kctd13 and 16p11.2 Del/+ mutant phenotypes in novel location and novel object recognition memory tests- Fasudil treatment restores the RhoA pathway in Kctd13+/- and 16p11.2 Del/+ models

P3-016: Chronic administration of CHF5074, a novel γ-secretase modulator, prevents brain neurodegeneration in aged Alzheimer's disease transgenic mice

2011 ◽  
Vol 7 ◽  
pp. S520-S520
Author(s):  
Sandra Sivilia ◽  
Luca Lorenzini ◽  
Alessandro Giuliani ◽  
Mercedes Fernandez ◽  
Marco Gusciglio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Chronic Administration

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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