Gut Inflammation Induced by Dextran Sulfate Sodium Exacerbates Amyloid-β Plaque Deposition in the App NL – G – F Mouse Model of Alzheimer’s Disease

Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and App NL - G - F mice at 6–10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and App NL - G - F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ 1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated App NL - G - F mice compared to vehicle treated App NL - G - F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system.

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P1-112: EFFECTS OF DEXTRAN SULFATE SODIUM-INDUCED COLITIS ON A MOUSE MODEL OF ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.115 ◽

2006 ◽

Vol 14 (7S_Part_5) ◽

pp. P314-P314

Author(s):

Mona Sohrabi ◽

Colin K. Combs

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Model Of Alzheimer’S Disease

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Cognitive Function Improvement in Mouse Model of Alzheimer’s Disease Following Transcranial Direct Current Stimulation

Brain Sciences ◽

10.3390/brainsci10080547 ◽

2020 ◽

Vol 10 (8) ◽

pp. 547

Author(s):

Wang-In Kim ◽

Jae-Young Han ◽

Min-Keun Song ◽

Hyeng-Kyu Park ◽

Jihoon Jo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Mouse Model ◽

Direct Current ◽

Transcranial Direct Current Stimulation ◽

Wild Type ◽

Direct Current Stimulation ◽

Induction Group ◽

The Brain

Anodal transcranial direct current stimulation (tDCS) is a painless noninvasive method that reportedly improves cognitive function in Alzheimer’s disease (AD) by stimulating the brain. However, its underlying mechanism remains unclear. Thus, the present study investigates the cognitive effects in a 5xFAD AD mouse model using electrophysiological and pathological methods. We used male 5xFAD C57BL/6J and male C57BL/6J wild-type mice; the dementia model was confirmed through DNA sequencing. The verified AD and wild-type mice were randomly assigned into four groups of five mice each: an induced AD group receiving tDCS treatment (Stim-AD), an induced AD group not receiving tDCS (noStim-AD), a non-induction group receiving tDCS (Stim-WT), and a non-induction group not receiving tDCS (noStim-WT). In the Stim group, mice received tDCS in the frontal bregma areas at an intensity of 200 µA for 20 min. After 2 weeks of treatment, we decapitated the mice, removed the hippocampus from the brain, confirmed its neuronal activation through excitatory postsynaptic potential (EPSP) recording, and performed molecular experiments on the remaining tissue using western blots. EPSP significantly increased in the Stim-AD group compared to that in the noStim-AD, which was comparable to that in the non-induced groups, Stim-WT and noStim-WT. There were no significant differences in cyclic amp-response element binding protein (CREB), phosphorylated CREB (pCREB), and Brain-derived neurotrophic factor (BDNF) levels in the Stim-AD group compared to those in the noStim-AD group. This study demonstrated that a tDCS in both frontal lobes of a transgenic 5xFAD mouse model affects long-term potentiation, indicating possible enhancement of cognitive function.

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Elevated Testosterone Level and Urine Scent Marking in Male 5xFAD Alzheimer Model Mice

Current Alzheimer Research ◽

10.2174/1567205017666200217105537 ◽

2020 ◽

Vol 17 (1) ◽

pp. 80-92 ◽

Cited By ~ 2

Author(s):

Lisa Gadomsky ◽

Malena dos Santos Guilherme ◽

Jakob Winkler ◽

Michael A. van der Kooij ◽

Tobias Hartmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sexual Behavior ◽

Mouse Model ◽

Cell Attachment ◽

Scent Marking ◽

Biochemical Properties ◽

Wild Type ◽

Testosterone Levels ◽

The Brain

Background: Function of the Amyloid Precursor Protein (AβPP) and its various cleavage products still is not unraveled down to the last detail. While its role as a source of the neurotoxic Amyloid beta (Aβ) peptides in Alzheimer’s Disease (AD) is undisputed and its property as a cell attachment protein is intriguing, while functions outside the neuronal context are scarcely investigated. This is particularly noteworthy because AβPP has a ubiquitous expression profile and its longer isoforms, AβPP750 and 770, are found in various tissues outside the brain and in non-neuronal cells. Objective: Here, we aimed at analyzing the 5xFAD Alzheimer’s disease mouse model in regard to male sexual function. The transgenes of this mouse model are regulated by Thy1 promoter activity and Thy1 is expressed in testes, e.g. by Sertoli cells. This allows speculation about an influence on sexual behavior. Methods: We analyzed morphological as well as biochemical properties of testicular tissue from 5xFAD mice and wild type littermates and testosterone levels in serum, testes and the brain. Sexual behavior was assessed by a urine scent marking test at different ages for both groups. Results: While sperm number, testes weight and morphological phenotypes of sperms were nearly indistinguishable from those of wild type littermates, testicular testosterone levels were significantly increased in the AD model mice. This was accompanied by elevated and prolonged sexual interest as displayed within the urine scent marking test. Conclusion: We suggest that overexpression of AβPP, which mostly is used to mimic AD in model mice, also affects male sexual behavior as assessed additional by the Urine Scent Marking (USM) test. The elevated testosterone levels might have an additional impact on central nervous system androgen receptors and also have to be considered when assessing learning and memory capabilities.

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Altered Brain Adiponectin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph13070150 ◽

2020 ◽

Vol 13 (7) ◽

pp. 150 ◽

Cited By ~ 1

Author(s):

Anishchal A. Pratap ◽

R. M. Damian Holsinger

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Receptor Expression ◽

Wild Type ◽

Model Of Alzheimer’S Disease ◽

Activated State ◽

5Xfad Mouse ◽

Neuronal Expression ◽

The Brain

Metabolic syndromes share common pathologies with Alzheimer’s disease (AD). Adiponectin, an adipocyte-derived protein, regulates energy metabolism via its receptors, AdipoR1 and AdipoR2. To investigate the distribution of adiponectin receptors (AdipoRs) in Alzheimer’s, we examined their expression in the aged 5XFAD mouse model of AD. In age-matched wild-type mice, we observed neuronal expression of both ARs throughout the brain as well as endothelial expression of AdipoR1. The pattern of receptor expression in the aged 5XFAD brain was significantly perturbed. Here, we observed decreased neuronal expression of both ARs and decreased endothelial expression of AdipoR1, but robust expression of AdipoR2 in activated astrocytes. We also observed AdipoR2-expressing astrocytes in the dorsomedial hypothalamic and thalamic mediodorsal nuclei, suggesting the possibility that astrocytes utilise AdipoR2 signalling to fuel their activated state in the AD brain. These findings provide further evidence of a metabolic disturbance and demonstrate a potential shift in energy utilisation in the AD brain, supporting imaging studies performed in AD patients.

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Faculty Opinions recommendation of GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725374290.793547530 ◽

2018 ◽

Author(s):

Michael Klymkowsky

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Transcriptional Response ◽

Wild Type ◽

Reactive Glia

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[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

Current Alzheimer Research ◽

10.2174/1567205015666181022095904 ◽

2018 ◽

Vol 16 (1) ◽

pp. 49-55 ◽

Cited By ~ 1

Author(s):

J. Stenzel ◽

C. Rühlmann ◽

T. Lindner ◽

S. Polei ◽

S. Teipel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

New Drugs ◽

Imaging Data ◽

Wild Type ◽

Preclinical Research ◽

Standardized Uptake Values ◽

Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

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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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