Identifying Vulnerable Brain Networks in Mouse Models of Genetic Risk Factors for Late Onset Alzheimer’s Disease

Badea, Alexandra; Wu, Wenlin; Shuff, Jordan; Wang, Michele; Qi, Yi; Johnson, G. Allan; Wilson, Joan G.; Koudoro, Serge; Garyfallidis, Eleftherios; Colton, Carol A.; Dunson, David B.

doi:10.3389/fninf.2019.00072

Cited by 29 publications

(40 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During recent decades, the sequential events that occur in the development and pathology of AD have been extensively studied, yet the precise etiology of the disease remains elusive, and current preventative and curative strategies are largely unsuccessful (Rong et al, 2017 ; Rasmussen and Langerman, 2019 ). Considering the complexity of AD pathology, it is apparent that other risk factors also exist besides those known, such as gender, education, smoking, dietary habit, depression, hypertension, diabetes mellitus, obesity, and head injury (Shinohara et al, 2014 ; Dursun et al, 2016 ; Badea et al, 2019 ; Jackson et al, 2019 ; Tapiainen et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics

Rong

Xiang

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Increasing evidence indicates Chronic Periodontitis (CP) is a comorbidity of Alzheimer's disease (AD), which is the most common form of age-related dementia, and for the latter, effective diagnostic and treatment strategies are lacking. Although inflammation is present in both diseases, the exact mechanisms and cross-links between CP and AD are poorly understood; and a direct association between the two has not been reported. This study aimed to identify a direct serum proteins link between AD and CP. Two-dimensional differential in-gel electrophoresis was employed to analyze serum samples from 12 CP patients and 12 age-matched controls. Furthermore, to determine the molecular link between CP and AD, neuroblastoma SK-N-SH APPwt cells were treated with 1 µg/ml of lipopolysaccharide from Porphyromonas gingivalis (P.g-LPS). Ten differentially expressed proteins were identified in CP patients. Among them, nine proteins were up-regulated, and one protein was down-regulated. Of the 10 differentially expressed proteins, five proteins were reportedly involved in the pathology of AD: Cofilin-2, Cathepsin B, Clusterin, Triosephosphate isomerase, and inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4). Western blotting indicated significantly higher expression of Cofilin-2, Cathepsin B, and Clusterin and lower expression of ITI-H4 in the CP group than in the Control group. The serum concentration of Cathepsin B has a good correlation with MMSE scores. Moreover, the protein level of Cathepsin B (but not that of ADAM10 and BACE1) increased significantly along with a prominent increase in Aβ 1-40 and Aβ 1-42 in the cell lysates of P.g-LPS-treated SK-N-SH APPwt cells. Cathepsin B inhibition resulted in a sharp decrease in Aβ 1-40 and Aβ 1-42 in the cell lysates. Furthermore, TNF-α was one of the most important inflammatory cytokines for the P.g-LPS-induced Cathepsin B upregulation in SK-N-SH APPwt cells. These results show that CP and AD share an association, while Cathepsin B could be a key link between the two diseases. The discovery of the identical serum proteins provides a potential mechanism underlying the increased risk of AD in CP patients, which could be critical for elucidating the pathophysiology of AD.

show abstract

Section: Introductionmentioning

confidence: 99%

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics

Rong

Xiang

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…And as noted above, comparison of clinical protocols with methods for the mouse brain is fraught. Retroviral tracers continue to be the gold standard for quantitative differentiation of afferent and efferent connections in the mouse brain 58 .Yet diffusion derived connectomes at microscopic resolution provide intriguing applications that cannot be done with tracers 9,13,59 . But like any new methodology, the protocols must be optimized and the limits understood.…”

Section: Resultsmentioning

confidence: 99%

A time-course study of actively stained mouse brains: DTI parameter and connectomic stability over one year

Xiao¹,

Hornburg

Cofer

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

While the application of diffusion tensor imaging (DTI), tractography, and connectomics to fixed ex-vivo tissue is a common practice today, there have been limited studies examining the effects of fixation on brain microstructure over extended periods. This time-course study reports the changes of regional brain volumes and diffusion scalar parameters, such as fractional anisotropy across twelve representative brain regions as measures of brain structural stability. The scalar DTI parameters and regional volumes were highly variable over the first two weeks after fixation. The same parameters were stable over a two to eight-week window after fixation which means confounds from tissue stability over that scanning window are minimal. Quantitative connectomes were analyzed over the same time period with extension out to one year. While there is some change in the scalar metrics at one year after fixation, these changes are sufficiently small, particularly in white matter to support reproducible connectomes over a period ranging from two weeks to one year post fixation. These findings delineate a stable scanning period during which brain volumes, diffusion scalar metrics and connectomes are remarkably stable.

show abstract

“…Further reductions in acquisition times come from compressed sensing [28], which several groups have implemented for mouse MRI [29][30][31]. Such advances can help translate diffusion protocols into population studies [32] incorporating multiple biomarkers from morphometry [33], microstructural properties based on diffusion [13] or magnetic susceptibility [34], or network properties [35]. Such integrative studies may better predict changes in behaviors, modeling those observed in humans with neurodegenerative conditions [34].…”

Section: Discussionmentioning

confidence: 99%

Optimizing Diffusion Imaging Protocols for Structural Connectomics in Mouse Models of Neurological Conditions

et al. 2020

Self Cite

View full text Add to dashboard Cite

Network approaches provide sensitive biomarkers for neurological conditions, such as Alzheimer's disease (AD). Mouse models can help advance our understanding of underlying pathologies, by dissecting vulnerable circuits. While the mouse brain contains less white matter compared to the human brain, axonal diameters compare relatively well (e.g., ∼0.6 µm in the mouse and ∼0.65-1.05 µm in the human corpus callosum). This makes the mouse an attractive test bed for novel diffusion models and imaging protocols. Remaining questions on the accuracy and uncertainty of connectomes have prompted us to evaluate diffusion imaging protocols with various spatial and angular resolutions. We have derived structural connectomes by extracting gradient subsets from a high-spatial, high-angular resolution diffusion acquisition (120 directions, 43-µm-size voxels). We have simulated protocols with 12, 15, 20, 30, 45, 60, 80, 100, and 120 angles and at 43, 86, or 172-µm voxel sizes. The rotational stability of these schemes increased with angular resolution. The minimum condition number was achieved for 120 directions, followed by 60 and 45 directions. The percentage of voxels containing one dyad was exceeded by those with two dyads after 45 directions, and for the highest spatial resolution protocols. For the 86-or 172-µm resolutions, these ratios converged toward 55% for one and 39% for two dyads, respectively, with <7% from voxels with three dyads. Tractography errors, estimated through dyad dispersion, decreased most with angular resolution. Spatial resolution effects became noticeable at 172 µm. Smaller tracts, e.g., the fornix, were affected more than larger ones, e.g., the fimbria. We observed an inflection point for 45 directions, and an asymptotic behavior after 60 directions, corresponding to similar projection density maps. Spatially downsampling to 86 µm, while maintaining the angular resolution, achieved a subgraph similarity of 96% relative to the reference. Using 60 directions with 86-or 172-µm voxels resulted in 94% similarity. Node similarity metrics indicated that major white matter tracts were more robust to downsampling relative to cortical regions. Our study provides guidelines for new protocols in mouse models of neurological conditions, so as to achieve similar connectomes, while increasing efficiency.

show abstract

Identifying Vulnerable Brain Networks in Mouse Models of Genetic Risk Factors for Late Onset Alzheimer’s Disease

Cited by 29 publications

References 59 publications

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics

A time-course study of actively stained mouse brains: DTI parameter and connectomic stability over one year

Optimizing Diffusion Imaging Protocols for Structural Connectomics in Mouse Models of Neurological Conditions

Contact Info

Product

Resources

About