High-resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer's disease mice

Abstract

Accumulating evidence indicates the critical importance of cerebrovascular dysfunction in the pathogenesis of Alzheimer's disease (AD). However, systematic comparative studies on the precise brain vasculature of wild-type and AD model mice are still rare. Using an image-optimization method for analysing Micro-Optical Sectioning Tomography (MOST) data, we generated cross-scale whole-brain 3D atlases that cover the entire vascular system from large vessels down to smallest capillaries at submicron resolution, for both wild-type mice and a transgenic (APP/PS1) mouse model of AD. In addition to distinct vascular patterns in different brain regions, we found that the main vessels of the molecular layer of the hippocampal dentate gyrus (DG-ml) undergo abrupt changes in both diameter and branch angle, spreading a unique comb-like pattern of capillaries. By using a quantitative analysis workflow, we identified in the hippocampus of AD mice an overall reduction of the mean vascular diameter, volume fraction and branch angle, with most significant impairment in the DG-ml. In addition, virtual endoscopy revealed irregular morphological features in the vessel lumen of the AD mice, potentially contributing to the impairment of blood flow. Our results demonstrate the capability of high-resolution cross-scale evaluation of brain vasculature and underscore the importance of studying hippocampal microcirculation for understanding AD pathogenesis.

Multi-Fluorescence High-Resolution Episcopic Microscopy (MF-HREM) for Three-Dimensional Imaging of Adult Murine Organs

“…This distribution is similar to the mean radius measured in other serial sectioning modalities e.g. MOST (49) and for clearing techniques (50) although no large vessels (>10 μm) are present in MF-HREM data, due to the preferential binding of lectin to microvasculature over larger vessels as noted previously (50).…”

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

“…In AD mouse models, live cortex imaging through a cranial window, or reconstructing the hippocampal vasculature of fixed brains, also showed a reduction of mean capillary diameter compared to normal mice [ 55 , 133 , 193 ], which in cortex reflected capillary constriction near pericyte somata [ 133 ]. Nortley et al [ 133 ] further demonstrated that, in the AD model mouse they used, neither arterioles nor venules had an altered diameter, implying that the reduction of CBF is generated by capillaries (although this still remains to be shown for human AD and other AD mouse models).…”

Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL

“…It remains unclear why the capillary thrombosis is mainly located in the cortex, instead of the striatum and hippocampus. It has been documented that the topological distribution of the capillary network is different throughout the brain to match the regional metabolism ( Shaw et al, 2019 ; Zhang et al, 2019 ). The vascular network shows distinct distribution and density in the cortex, hippocampus and striatum.…”

“…The cortical parenchyma is full of abundant vessels, which are well arranged into a mesh-like network. The vascular density in the hippocampus is significantly lower than the cortical vessel density ( Zhang et al, 2019 ). No obvious difference of vascular density is seen between the striatum and cortex ( Di Giovanna et al, 2018 ).…”