Progressive Vascular Abnormalities in the Aging 3xTg-AD Mouse Model of Alzheimer's Disease (original) (raw)
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Biomedicines
Amyloid β (Aβ) peptide is deposited in the brains of sporadic Alzheimer’s disease (AD) due to impaired vessel-dependent clearance. To understand the mechanisms, we investigated time-dependent cerebrovascular changes in AD model mice. Cerebrovascular and other pathological changes were analyzed in AD model mice (J20 strain) aging from 2 to 9 months by immunostaining. At 2 months, Aβ was only intraneuronal, whereas vessels were positive from 3 months in J20 mice. Compared to wild-type (WT), vessel density was increased at 2 months but decreased at 9 months in J20 mice, claudin-5 levels were decreased, and vascular endothelial growth factor (VEGF) levels were increased in the cortex and hippocampus of J20 mice brain at all time points. Albumin extravasation was evident from 3 months in J20 brains. Collagen 4 was increased at 2 and 3 months. Aquaporin 4 was spread beyond the vessels starting from 3 months in J20, which was restricted around the vessel in wild-type mice. In conclusion, t...
Imaging of cerebrovascular pathology in animal models of Alzheimer's disease
Frontiers in Aging Neuroscience, 2014
Klohs et al. Cerebrovascular imaging in AD models IMAGING MODALITIES FOR THE CHARACTERIZATION OF CEREBRAL VASCULATURE Multimodal imaging offers an impressive number of approaches for characterizing cerebral vasculature from the cellular to the whole organ scale (Table 2). The dimensions of cerebral vessels span a range of 2-3 orders of magnitude with large arteries and veins of dimensions of approximately 1 mm to capillaries with typical diameters of 5-10 μm. Correspondingly, the phenotypic
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
Neuropathological changes associated with Alzheimer's disease (AD) such as amyloidplaques, cerebral amyloid angiopathy, and related pathologies are reproduced in APP23 transgenic mice overexpressing amyloid precursor protein (APP) with the Swedish mutation. Magnetic resonance angiography (MRA) was applied to probe, in vivo, the cerebral arterial hemodynamics of these mice. Flow voids were detected at the internal carotid artery of 11-month-old APP23 mice. At the age of 20 months, additional flow disturbances were observed in large arteries at the circle of Willis. Vascular corrosion casts obtained from the same mice revealed that vessel elimination, deformation, or both had taken place at the sites where flow voids were detected by MRA. The detailed three-dimensional architecture of the vasculature visible in the casts assisted the identification of smaller vessels most likely formed as substitution or anastomosis within the circle of Willis. Angiograms and corrosion casts from ...
Journal of Neuropathology & Experimental Neurology, 2019
We describe age-related histological structure and molecular changes of the neurovascular unit (NVU) in the cerebral cortex of Tg2576 and age-matched wild-type (WT) mice. Major results can be summarized as follows: (i) b-amyloid (6E10)-immunoreactivity progressively increases in neurons and astrocytes of Tg2576 mice, reaching the highest concentration at 5 months and then decreasing as soon as extracellular plaque deposition begins; (ii) the synaptic puncta density of glutamatergic and GABAergic neurons in Tg2576 mice is unbalanced versus WT at all investigated ages, with a decrease in synaptophysin and VGLUT1; density of VGAT contacts is higher in 27-month-old Tg2576 versus WT mice; (iii) capillary density is higher in 5-month-old Tg2576 versus WT mice, then decreases to a lower density at 27 months, when the capillaryastrocyte interface is lower; and (iv) mRNA expression of genes involved in microvessel dynamics indicates age-and genotypedependent changes in the expression levels of hypoxia-related genes, i.e. the highest level is in 5-month-old animals and there is impaired regulation in Tg2576. We conclude that at 5 months, when learning and memory impairment is already present in the absence of extracellular amyloid plaque deposition, Tg2576 mice display alterations in the structure and molecular regulation of the NVU.
Brain Structure and Function, 2013
Vascular disorders can either be cause or consequence in the pathophysiology of Alzheimer's disease (AD). To comprehensively characterize the occurrence of vascular impairment in a double transgenic mouse model for AD (APP swe /PS1 dE9) during aging, we developed a new method to obtain microvascular relative cerebral blood volume (rCBV micro) maps from gradient echo MR imaging by histogram evaluation and we applied a voxel-wise approach to detect rCBV micro changes. With this methodology the development of cerebral microvascular impairments can be described in vivo with 0.16 mm isotropic resolution for the whole mouse brain. At 8 months, impaired rCBV micro appeared in some cortical regions and in the thalamus, which spreads over several sub-cortical areas and the hippocampus at 13 months. With a ROI-based approach, we further showed that hippocampal rCBV micro in 13-month-old wildtype and APP swe /PS1 dE9 mice correlates well with capillary density measured with immunohistochemical staining. However, no differences in capillary density were detected between genotypes. The rCBV micro values showed no significant correlation with amyloid-b (Ab) plaque deposition, Ab at blood vessel walls and biochemically measured levels of Ab 1-40 , Ab 1-42 oligomers and fibrillar forms. These results suggest that rCBV micro reduction is caused by an impaired vasoactivity of capillaries and arterioles, which is not directly correlated with the amount of Ab deposition in parenchyma nor blood vessel walls.