Abstract
Vascular dementia is the second leading form of dementia after Alzheimer’s disease. There is a relative lack of animal models in which to study the mechanisms underlying cerebrovascular disease leading to dementia. In addition, cerebrovascular disease is a common co-morbidity in Alzheimer’s patients, yet its impact on Alzheimer’s pathology and clinical outcome is unknown. We aimed to develop a model of vascular dementia that could allow us to create a model of cerebrovascular disease / amyloid pathology co-morbidity. We Induced hyperhomocysteinemia through dietary deficiency of B-vitamins and enrichment of methionine in 3 month old wildtype mice for fourteen weeks. We also used the same methods to induce hyperhomocysteinemia in 6 month old APP/PS1 mice for four and six months. We performed T2* MRI, histology and biochemistry to assess outcomes. In the wildtype mice on diet for fourteen weeks we observed significant microhemorrhages by T2* MRI imaging that was confirmed by Prussian blue staining. We found that the MRI detects a smaller number of microhemorrhages than does the Prussian blue staining. The hyperhomocysteinemic mice had significant neuroinflammation, as demonstrated by increased expression of IL-1β, TNFα, IL-6 and IL-12. Importantly, we found increased expression and activity of the matrix metalloproteinases MMP2 and MMP9. In the APP/PS1 mice we have found that hyperhomocysteinemia induces an increase in total brain Aβ, detected both biochemically and immunohistochemically. Of note, was a greater increase in Aβ1-40 than Aβ1-42. We have also found increased cerebral amyloid angiopathy with hyperhomocysteinemia, and an exacerbated neuroinflammatory response. The numbers of microhemorrhages were comparable between wildtype and APP/PS1 hyperhomocysteinemic mice, but the microhemorrhages appear larger in the APP/PS1 mice. Overall, we believe our data indicates that cerebrovascular disease co-morbid with amyloid pathology, exacerbates the cerebrovascular amyloid pathology and could have implications to therapeutic development for the treatment of Alzheimer’s disease.
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