High precision whole brain vascular map reveals the damage of cerebral vessels in Alzheimer's disease model mice

Alzheimer's disease (AD) is a serious degenerative disease of the central nervous system In clinic, there is a lack of drugs and interventions that can effectively delay or reverse the disease process, which seriously harms the health and quality of life of the elderly, and brings a huge burden to the family and society There are many hypotheses about the pathogenesis of AD, such as cholinergic defect, β - amyloid cascade reaction, tau protein hyperphosphorylation, etc However, the single acting mechanism drugs developed for these hypotheses have not achieved ideal clinical efficacy, suggesting that human recognition of the pathogenesis of ad still has great limitations, and new breakthrough means need to be explored Jiang Hualiang, Gao zhaobing and Zhang Haiyan, Shanghai Institute of medicine, Chinese Academy of Sciences, conducted the research on the pathogenesis of AD and anti ad drugs Recently, in the national science review, high resolution m app ing of brain neuroscience and its improvement in the hippocampus of Alzheimer's disease mice was published The results showed that the vascular system in the brain of AD model mice, especially in the hippocampus, was significantly damaged, suggesting that the importance of vascular damage in the pathological process of AD was far from fully recognized, which pointed out a new direction for the development of high-efficiency AD treatment drugs and interventions The construction of the whole cerebrovascular network, especially the high-precision analysis of the microcirculation system, is the prerequisite for the achievement of this research Before that, there are still many challenges to realize the whole brain scale high-resolution imaging, low signal-to-noise ratio image data enhancement, high spatial complexity 3D image data visualization and quantitative analysis In this work, the research team applied the original most technology developed by Luo Qingming, a professor of Huazhong University of science and technology, and obtained the app for the first time at the resolution level of 0.35 × 0.35 × 1.00 μ M /The whole brain data set of the PS1 transgenic AD model mice (TG AD) was used to optimize the image after preprocessing by the algorithm developed by the team itself, and a complete cross-scale 3D blood vessel map of the whole brain of mice was constructed, which included the large blood vessels with diameters of tens of microns to the capillaries with diameters less than 2 microns (Fig 1 and video 1) Through the systematic quantitative analysis of the cerebral vascular network of AD model and wild-type mice, it was found that the average vascular diameter and volume fraction (volume of blood vessels per unit volume of tissue) of hippopotamus decreased significantly in AD model mice Further comparative analysis of different subregions of the hippocampus revealed that the decrease of mean vessel diameter, vessel length density (vessel length per unit volume of tissue) and vessel volume fraction in the molecular layer of dentate gyrus (DG ml) was the most significant (Fig 2) In addition, the results of quantitative analysis of single vessel branching pattern showed that in addition to the thinning and reduction of vessels, the angle of vessel branching in AD model mice significantly decreased, resulting in the decrease of blood perfusion area of single hippocampal vessels Using the virtual vascular endoscopy technology pioneered by the research team, the study further revealed that there were significant differences between AD model and wild-type mice in the roughness of the lumen inner wall and the smoothness of the branch nodes (see Figure 3 and Video 2) The above results show that cerebral vascular system and hippocampal microcirculation play an important role in the pathological process of AD In order to carry out this research, Shanghai Pharmaceutical Institute has set up an interdisciplinary research team with multi-disciplinary backgrounds including computer image processing, neuropharmacology, drug research and development, focusing on the construction and analysis of high-precision microvascular atlas, developing an efficient image optimization algorithm for background correction, noise suppression, contrast enhancement of coronal data, and building a fast and high-precision three-dimensional Based on the software and hardware platform of rendering and morphological quantitative analysis of microstructure, 3D atlas data mining of TB scale (trillion bytes, 20000 × 30000 × 12000 voxels) is realized After the quantitative analysis of the whole cerebral vascular network of 2-month-old wild-type mice, the research team found that there was a complex vascular network with a total length of more than 300 meters in the brain tissue of no more than 0.2 cubic cm, and there were significant differences in the distribution and morphological characteristics of blood vessels in different brain regions In addition, compared with the cortex, thalamus and other brain regions, the average vascular diameter, vascular length density and vascular volume fraction of hippocampus were the lowest Through high-precision visualization of the whole hippocampal blood vessels, it is found that the transverse blood vessels of the whole hippocampal are distributed in a rake like parallel pattern perpendicular to the longitudinal axis of the hippocampus In addition, the diameter of the main vessels in the molecular layer of the dentate gyrus of the hippocampus decreased sharply after they separated from the superior main vessels, and they were also close to a right angle in the branching angle (Fig 1) This unique pattern of comb like branches is obviously different from that of other hippocampal subregions The special branching pattern of the molecular layer of dentate gyrus in hippocampus may make it more vulnerable to injury, which is also consistent with the reduction of the average vascular diameter, vascular length density and vascular volume fraction of the molecular layer of dentate gyrus in AD model mice The high-resolution cross-scale visualization and quantitative analysis ability developed in this study can not only be applied to the study of cerebral blood vessels in mice, but also can be applied to the study of cerebral blood vessels in rats, monkeys and humans with a larger spatial scale, which is helpful for the comprehensive analysis of the correlation between brain related diseases and vascular system damage.