scholarly journals The Dual GLP-1/GIP Receptor Agonist DA4-JC Shows Superior Protective Properties Compared to the GLP-1 Analogue Liraglutide in the APP/PS1 Mouse Model of Alzheimer’s Disease

2020 ◽  
Vol 35 ◽  
pp. 153331752095304
Author(s):  
Mark Maskery ◽  
Elizabeth Mary Goulding ◽  
Simon Gengler ◽  
Josefine Ulrikke Melchiorsen ◽  
Mette Marie Rosenkilde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Receptor Agonist ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Amyloid Plaques ◽  
Model Of Alzheimer’S Disease ◽  
The Brain ◽  
Gip Receptor

Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is no cure. Here, we test a dual GLP-1/GIP receptor agonist (DA4-JC) that has a cell penetrating sequence added to enhance blood-brain barrier penetration. We show in a receptor activity study that DA4-JC has balanced activity on both GLP-1 and GIP receptors but not on GLP-2 or Glucagon receptors. A dose-response study in the APP/PS1 mouse model of AD showed both a dose-dependent drug effect on the inflammation response and the reduction of amyloid plaques in the brain. When comparing DA4-JC with the GLP-1 analogue liraglutide at equal doses of 10nmol/kg bw ip. once-daily for 8 weeks, DA4-JC was more effective in reversing memory loss, enhancing synaptic plasticity (LTP) in the hippocampus, reducing amyloid plaques and lowering pro-inflammatory cytokine levels in the brain. The results suggest that DA4-JC may be a novel treatment for AD.

scholarly journals The dual GLP‐1/GIP receptor agonist DA4‐JC shows superior protective properties in the APP/PS1 mouse model of Alzheimer’s disease

2020 ◽  
Vol 16 (S9) ◽  
Author(s):  
Mark Maskery ◽  
Simon Gengler ◽  
Elizabeth Mary Goulding ◽  
Josefine Ulrikke Melchiorsen ◽  
Mette M. Rosenkilde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Receptor Agonist ◽  
Protective Properties ◽  
Model Of Alzheimer’S Disease ◽  
Gip Receptor

scholarly journals IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1605
Author(s):  
Anna Escrig ◽  
Amalia Molinero ◽  
Brenda Méndez ◽  
Mercedes Giralt ◽  
Gemma Comes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Metabolic Phenotype ◽  
Soluble Form ◽  
Dependent Manner ◽  
Model Of Alzheimer’S Disease ◽  
The Brain ◽  
Ad Mouse Model

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.

scholarly journals Intermittent Hypoxic Conditioning Rescues Cognition and Mitochondrial Bioenergetic Profile in the Triple Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (1) ◽  
pp. 461
Author(s):  
Sónia C. Correia ◽  
Nuno J. Machado ◽  
Marco G. Alves ◽  
Pedro F. Oliveira ◽  
Paula I. Moreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Brain Cortex ◽  
Neurodegenerative Disorder ◽  
Special Focus ◽  
Mitochondrial Bioenergetics ◽  
Related Phenotype ◽  
Brain Resilience ◽  
The Brain

The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.

A fingerprint of amyloid plaques in a bitransgenic animal model of Alzheimer's disease obtained by statistical unmixing analysis of hyperspectral Raman data

The Analyst ◽  
2019 ◽  
Vol 144 (23) ◽  
pp. 7049-7056 ◽  
Author(s):  
Emerson A. Fonseca ◽  
Lucas Lafetá ◽  
Renan Cunha ◽  
Hudson Miranda ◽  
João Campos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Amyloid Plaques ◽  
Model Of Alzheimer’S Disease ◽  
The Brain ◽  
Brain Tissues

We have found different Raman signatures of AB fibrils and in brain tissues from unmixed analysis, providing a detailed image of amyloid plaques in the brain, with the potential to be used as biomarkers.

scholarly journals Studies of copper trafficking in a mouse model of Alzheimer's disease by positron emission tomography: comparison of64Cu acetate and64CuGTSM

Metallomics ◽  
2017 ◽  
Vol 9 (11) ◽  
pp. 1622-1633 ◽  
Author(s):  
Erica M. Andreozzi ◽  
Julia Baguña Torres ◽  
Kavitha Sunassee ◽  
Joel Dunn ◽  
Simon Walker-Samuel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Mouse Model ◽  
Amyloid Plaques ◽  
Emission Tomography ◽  
Copper Trafficking ◽  
Model Of Alzheimer’S Disease ◽  
Positron Emission ◽  
Selective Delivery

Positron emission tomography with64Cu demonstrates regionally selective delivery of copper to brain, which although modified in an Alzheimer's model, does not correlate with the location of amyloid plaques.

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