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

Abstract

IntroductionVascular 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 comorbid with their AD pathology. We hypothesized that cerebrovascular disease significantly impacts AD pathological progression.MethodsWe 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 present study, we induced HHcy in APP/PS1 transgenic mice.ResultsWhile total β-amyloid (Aβ) 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 mice than in the wild-type mice and that it switched the neuroinflammatory phenotype from an M2a biased state to an M1 biased state. Associated with these changes was an induction of the matrix metalloproteinase protein 2 (MMP2) and MMP9 systems. Interestingly, after 6 months of HHcy, the APP/PS1 mice were cognitively worse than wild-type HHcy mice or APP/PS1 mice, indicative of an additive effect of the cerebrovascular pathology and amyloid deposition.ConclusionsThese data show that cerebrovascular disease can significantly impact Aβ 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 the efficacy of therapeutics.

Animal Models of Vascular Cognitive Impairment and Dementia (VCID)

“…Mice with 6-12 months of age exhibit significant elevations in plasma homocysteine levels in both WT and APP/PS1 mice when fed this diet (Sudduth et al 2013). Sudduth et al (2014) found in APP/PS1 mice with moderate HHcy, HHcy did not affect Ab levels, but deposition of amyloid was more associated with the vasculature. In the frontal cortex and hippocampus, there was a 50-60 % reduction in parenchymal amyloid and over double the amount of CAA in HHcy APP/PS1 mice relative to control APP/PS1 mice.…”

“…Severe suppression of microglia by high methionine intake is associated with a very mild HHcy compared to a modest suppression of microglia by B-vitamin deficiency associated with a severe HHcy (Troen et al 2007). Mice with moderate HHcy displayed significant induction of microhemorrhages and a neuroinflammatory phenotype switch from a repair-like state to a pro-inflammatory state in both WT and APP/PS1 mice (Sudduth et al 2014).…”

“…MMP9 is a critical mediator for hemorrhagic transformation following a cerebral ischemic event, white matter lesion formation, and blood-brain barrier (BBB) breakdown in VCID (Sudduth et al 2014). Increased expression and activity of MMP2 and MMP9 systems were associated with cerebral hemorrhage resulting from CAA (Lentz et al 2000;Sudduth et al 2013).…”

Quantitative analysis of the capillary network of aged APPswe/PS1dE9 transgenic mice

“…(Hooijmans, et al, 2007). A similar ratio of parenchymal to vascular associated amyloid is seen in this mouse at 12 months of age (Sudduth, et al, 2014). A photo micograph of a 205…”

CSF biomarkers in neurodegenerative and vascular dementias

“…Several models linking the b-amyloid hypothesis of AD and cerebral vascular pathology have been proposed (van Norden et al, 2012). On one hand, vascular pathology affects the age of onset of cognitive impairment and dementia in AD (de la Torre, 2004) likely due, at least in part, to altered b-amyloid clearance (ElAli et al, 2013;Sudduth et al, 2014). On the other hand, b-amyloid deposition in blood vessels produces secondary vascular lesions (van Norden et al, 2012).…”