Key result
Aging Alzheimer mice show a ~50% drop in cerebral total hemoglobin alongside severe microvascular rarefaction.
Why the study?
Does amyloid-β pathology in the 3xTg-AD mouse model impair in vivo cerebral hemodynamics, vascular volume fraction, and vessel density across aging compared to age-matched control mice?
Does amyloid-β pathology in the 3xTg-AD mouse model impair in vivo cerebral hemodynamics, vascular volume fraction, and vessel density across aging compared to age-matched control mice?
Multimodal optical imaging in 3xTg-AD mice demonstrates that cerebral hypoxia and perfusion deficits emerge as early as 8 months and progress to severe vascular volume and density loss by 20 months despite VEGF and eNOS upregulation, implicating amyloid-β in blocking endogenous vascular repair.
Answers are grounded in this paper and cite their sources.
Progressive cerebral hypoxia and vascular rarefaction emerge early in AD mice; hypothesis-generating for human translation and should not change practice.
Alzheimer’s disease (AD) and cerebrovascular disease are often comorbid conditions, but the relationship between amyloid-β and in vivo vascular pathophysiology is poorly understood. We utilized a multimodal, multiscale optical imaging approach, including spatial frequency domain imaging, Doppler optical coherence tomography, and confocal microscopy, to quantify AD-dependent changes in a triple transgenic mouse model (3xTg-AD) and age-matched controls. From three months of age (naïve) to 20 months (severe AD), the brain tissue concentration of total and oxy-hemoglobin (Total Hb, ctO2Hb) decreased 50 and 70%, respectively, in 3xTg-AD mice. Compared to age-matched controls, significant differences in brain hemoglobin concentrations occurred as early as eight months (Total Hb: 126±5 μM versus 108±4 μM; ctO2Hb: 86±5 μM versus 70±3 μM; for control and AD, respectively). These changes were linked to a 29% vascular volume fraction decrease and 35% vessel density reduction in the 20-month-old 3xTg-AD versus age-matched controls. Vascular reduction coincided with increased brain concentration of amyloid-β protein, vascular endothelial growth factor (VEGF), and endothelial nitric oxide synthase (eNOS) at eight and 20 months compared to the three-month baseline. Our results suggest that amyloid-β blocks the normally reparative effects of upregulated VEGF and eNOS, and may accelerate in vivo vascular pathophysiology in AD.
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Lin et al. (2014) studied Alzheimer's disease (triple transgenic 3xTg-AD mouse model) (n=41). 3xTg-AD transgenic mouse genotype (amyloid-beta and tau pathology) evaluated via multimodal optical imaging vs. Age-matched C57 BL/6-129svj control mice was evaluated on Brain tissue total hemoglobin concentration (Total Hb, μM) at 20 months (p=<0.01). 3xTg-AD mice exhibited a 50% decrease in brain total hemoglobin and 70% decrease in oxy-hemoglobin from 3 to 20 months, alongside a 29% lower vascular volume fraction (p=0.03) and 35% lower vessel density (p<0.05) vs controls at 20 months.
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