What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues?

Organizational and activational effects of sex steroids were first discovered in laboratory animals, but these concepts extend to hormonal actions in the human central nervous system. This chapter begins with a brief overview of how sex steroids act in the brain and how the organizational-activational hypothesis originated in the field of endocrinology. It then reviews common methods used to study these effects in humans. Interestingly, certain cognitive functions appear to be subject to modification by sex steroids, and these endocrine influences may help explain the sex differences often seen in these functions. The chapter considers spatial cognition as a representative example because the spatial family of functions has received the most study by researchers interested in the biological roots of sex differences in cognition. The chapter reviews evidence that supports an influence of both androgens and estrogens on spatial functions, and concludes with a glimpse of where the field is headed.

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Long-term voluntary running modifies the levels of proteins of the excitatory/inhibitory system and reduces reactive astrogliosis in the brain of Ts65Dn mouse model for Down syndrome

Brain Research ◽

10.1016/j.brainres.2021.147535 ◽

2021 ◽

pp. 147535

Author(s):

Elizabeth Kida ◽

Marius Walus ◽

Giorgio Albertini ◽

Adam A. Golabek

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Ts65dn Mouse ◽

Inhibitory System ◽

Reactive Astrogliosis ◽

Voluntary Running ◽

The Brain

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

International Journal of Molecular Sciences ◽

10.3390/ijms22010461 ◽

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.

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Preclinical Detection of Alpha-Synuclein Seeding Activity in the Colon of a Transgenic Mouse Model of Synucleinopathy by RT-QuIC

Viruses ◽

10.3390/v13050759 ◽

2021 ◽

Vol 13 (5) ◽

pp. 759

Author(s):

Jung-Youn Han ◽

Chaewon Shin ◽

Young Pyo Choi

Keyword(s):

Mouse Model ◽

Transgenic Mice ◽

Lewy Body ◽

Dementia With Lewy Body ◽

Transgenic Mouse Model ◽

Alpha Synuclein ◽

Gi Tract ◽

Colon Tissue ◽

Presymptomatic Stage ◽

The Brain

In synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy body (DLB), pathological alpha-synuclein (α-syn) aggregates are found in the gastrointestinal (GI) tract as well as in the brain. In this study, using real-time quaking-induced conversion (RT-QuIC), we investigated the presence of α-syn seeding activity in the brain and colon tissue of G2-3 transgenic mice expressing human A53T α-syn. Here we show that pathological α-syn aggregates with seeding activity were present in the colon of G2-3 mice as early as 3 months old, which is in the presymptomatic stage prior to the observation of any neurological abnormalities. In contrast, α-syn seeding activity was not detectable in 3 month-old mouse brains and only identified at 6 months of age in one of three mice. In the symptomatic stage of 12 months of age, RT-QuIC seeding activity was consistently detectable in both the brain and colon of G2-3 mice. Our results indicate that the RT-QuIC assay can presymptomatically detect pathological α-syn aggregates in the colon of G2-3 mice several months prior to their detection in brain tissue.

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UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation

Nature Communications ◽

10.1038/s41467-021-23597-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Manivannan Subramanian ◽

Seung Jae Hyeon ◽

Tanuza Das ◽

Yoon Seok Suh ◽

Yun Kyung Kim ◽

...

Keyword(s):

Mouse Model ◽

Ubiquitin Ligase ◽

Therapeutic Approach ◽

Target Gene ◽

Neuroblastoma Cells ◽

E3 Ligase ◽

Tau Hyperphosphorylation ◽

Phosphorylated Tau ◽

Major Pathway ◽

The Brain

AbstractThe formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer’s disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.

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Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

Current Developments in Nutrition ◽

10.1093/cdn/nzaa155 ◽

2020 ◽

Vol 4 (11) ◽

Author(s):

Katherine M Ranard ◽

Matthew J Kuchan ◽

John W Erdman

Keyword(s):

Animal Model ◽

Vitamin E ◽

Mouse Model ◽

Wild Type ◽

Future Studies ◽

Neurological Outcomes ◽

Transfer Protein ◽

And Function ◽

The Brain ◽

Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

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