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Published on: March 22, 2016
Modeling Mixed Vascular and Alzheimer's Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD
Eric Y Hayden1, Julia M Huang1, Malena Charreton1
1Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 635 Charles E. Young Dr. South, Neuroscience Research Building, Rm 415, Los Angeles, CA, 90095, USA.
Abstract:
Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.
Insights
Subcortical ischemic stroke reduced amyloid plaques and improved cognition in a novel Alzheimer's disease (AD) mouse model. Activated microglia in the cortex suggest a mechanism for amyloid clearance in mixed dementia.
Area of Science:
- Neuroscience
- Pathology
- Dementia Research
Background:
- Subcortical white matter ischemic lesions and Alzheimer's disease (AD) pathology often co-occur.
- The interaction between ischemic lesions and AD's amyloid pathology is not well understood.
Purpose of the Study:
- To develop and utilize a novel mouse model to investigate the mechanisms of mixed vascular and AD dementia.
- To explore the effects of subcortical ischemic stroke on amyloid pathology and cognitive function in a mouse model of AD.
Main Methods:
- A mouse model combining subcortical white matter ischemic stroke and AD pathology (ApoE4-TR:5XFAD mice) was created.
- Stereotactic injection of an eNOS inhibitor induced stroke; behavioral tests and 18FDG-PET/CT were performed.
- Brain tissue was analyzed for amyloid plaques and microglial activation (Iba-1+ cells).
Main Results:
- Mice with subcortical ischemic stroke showed significantly reduced amyloid plaque burden compared to sham controls.
- Cognitive performance was improved in the stroke group.
- Increased numbers and complexity of Iba-1+ microglia were observed in the cortex overlying the stroke area.
Conclusions:
- Subcortical ischemic stroke may reduce amyloid burden in AD mouse models.
- Activated microglia interacting with cortical neurons might promote amyloid clearance.
- This model offers insights into the interplay between vascular and AD pathologies in dementia.
