Modeling Mixed Vascular and Alzheimer’s Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD Transgenic Mice

Eric Y. Hayden, Julia M. Huang, Malena Charreton, Stefanie M. Nunez, Jennifer N. Putman, Bruce Teter, Jason T. Lee, Andrew Welch, Sally Frautschy, Gregory Cole, Edmond Teng, Jason D. Hinman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1064-1076
Number of pages13
JournalTranslational Stroke Research
Issue number5
Early online date21 Feb 2020
Publication statusPublished - Oct 2020

Bibliographical note


Behavioral experiments were conducted in the UCLA Behavior Testing Core under the supervision of Drs. Jesse Cushman, Abha Karki Rajbhandari and conducted by Irina Zhuravka.

This study was funded by NINDS NS083740 (JDH), the American Federation for Aging Research/Rosalind and Arthur Gilbert Foundation New Investigator in Alzheimer’s disease award (JDH), the National Center for Advancing Translational Sciences UCLA CTSI Grant UL1TR000124, the Brain Research Institute, the American Heart Association Undergraduate Student Research Program (JMH), and generous gifts from the Paul Slavik Foundation, The Sam and Ida Turken Charitable Foundation (EYH), and support from the UCLA Department of Neurology.


  • Alzheimer’s disease
  • Amyloid
  • Lacunar stroke
  • Modeling
  • White matter disease
  • A-BETA
  • Alzheimer's disease


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