Multi-scale Assessment of Brain Blood Volume and Perfusion in the APP/PS1 Mouse Model of Amyloidosis

Abstract

ABSTRACTVascular dysfunction is increasingly recognized to play a role in the development of Alzheimer’s disease (AD). The relation between vascular dysfunction and the neuropathological amyloid β accumulation characteristic for AD is however unclear. The limited resolution of in vivo imaging techniques, the intricate 3D structure of the microvasculature and the different co-occurring types of amyloid β accumulation in patients hamper studying this relation in patients. Here, we therefore employed the APP/PS1 mouse model, which develops parenchymal amyloid β plaques, to study the effect of parenchymal amyloid β plaques on the structure and function of the vasculature. Blood vessels and amyloid β plaques were fluorescently labeled in vivo with lectin-DyLight594 and methoxy XO4, respectively, in APP/PS1 mice at old age. The brain tissue was cleared post-mortem with the CUBIC clearing protocol, which allowed structural imaging at microscopic resolution of the vessels and plaques in a large 3D volume. Segmentation of the vasculature enabled mapping of the microvascular Cerebral Blood Volume (mCBV), which ranged from 2 % to 5 % in the white matter and the thalamus, respectively. No mCBV differences were observed between APP/PS1 mice and wild type (WT) control mice. The effect of the amyloid β plaques on vascular function was studied in vivo by measuring Cerebral Blood Flow (CBF) and Arterial Transit Time (ATT) with Arterial Spin Labeling (ASL) MRI. Similar to the mCBV findings, no differences were observed in CBF or ATT between APP/PS1 and control mice, indicating that brain vascular morphology and function in this mouse model are preserved in the presence of amyloid β plaques.