Comorbidity to dementia: The contributions of focal subclinical ischemia to pathogenesis in a mouse model of Alzheimer’s disease

Background Although stroke and Alzheimer’s disease (AD) are distinctly different diseases, the risk for both substantially increase with aging, with stroke survivors being twice as likely to develop dementia. Although subclinical ischemic events do not present with outward symptoms, they share similar risk factors and outnumber overt ischemic events >9 to 1, with 31% of adults over the age of 65 experiencing at least one such event. The ischemic cascade may initiate neuropathological changes, leading to an increased susceptibility to develop AD. Hence, there is a need to elucidate the relationship between subclinical ischemia and AD pathogenesis. Method The endothelin‐1 (ET1) model of ischemia was utilized for subclinical focal stroke induction, while the inducible APPsi:tTA mouse was used to model AD, as it allows for temporal control of APP gene expression. To examine the impact of focal ischemia on AD, bigenic (tTA/APP) (DTg) and control (tTA) mice underwent unilateral stereotaxic ET1 or sham (vehicle) surgery in the medial prefrontal cortex and allowed to recover, before turning on APP gene expression. Structural MRI one week following surgery allowed for evaluation of the size and location of the stroke. Behavioral tests were performed to examine for changes as a result of subclinical focal ischemia and post‐APP expression. Immunohistochemistry and immunofluorescence were conducted for changes in amyloid load (6F/3D), astrocytes (GFAP), microglia (Iba1) 7 weeks post‐APP expression. Result Analysis of MRI confirmed the presence of subclinical ischemic events in ET1 DTg tTA mice. ET1 DTg animals showed significant behavioral deficits in marble burying, nest‐building, open field and Y‐maze, post expression of APP when compared to tTA controls. DTg animals also showed an increase in astrocyte and microglial activation post‐APP expression, but no differences were found in amyloid load between ET1 DTg and sham DTg animals. Conclusion The APPsi‐tTA mouse model allowed for controlled APP transgene expression– where the AD pathogenesis occurs independently after the initial subclinical event. Results show that subclinical ischemic insult to the brain enhance AD pathogenesis and allow for better understanding of the impact of comorbidities to AD progression.