Beta-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice.

Introduction Vascular dementia is the second most common cause of dementia after Alzheimer's disease (AD). In addition, it is estimated that almost half of all AD patients have significant cerebrovascular disease co-morbid with their AD pathology. We hypothesized that cerebrovascular disease significantly impacts AD pathological progression. Methods We used a dietary model of cerebrovascular disease that relies on the induction of hyperhomocysteinemia (HHCy). HHCy is a significant clinical risk factor for stroke, cardiovascular disease and type 2 diabetes. In the current study we induced HHCy in APP/PS1 transgenic mice. Results While total beta-amyloid (Abeta) load is unchanged across groups, Congophilic amyloid deposition was decreased in the parenchyma and significantly increased in the vasculature as cerebral amyloid angiopathy (CAA; vascular amyloid deposition) in HHCy APP/PS1 mice. We also found that HHCy induced more microhemorrhages in the APP/PS1 than the wildtype mice and switched the neuroinflammatory phenotype from an M2a biased state to an M1 biased state. Associated with these changes was an induction of the MMP2 and MMP9 systems. Interestingly, after 6 months of HHCy, the APP/PS1 mice were cognitively worse than wildtype HHCy or APP/PS1 mice, indicative of an additive effect of the cerebrovascular pathology and the amyloid deposition. Conclusions These data show that cerebrovascular disease can significantly impact Abeta distribution in the brain, favoring vascular deposition. We predict that the presence of cerebrovascular disease with AD will have a significant impact on AD progression and efficacy of therapeutics. [ABSTRACT FROM AUTHOR]