In vivo characterization of spontaneous microhemorrhage formation in mice with cerebral amyloid angiopathy

Abstract

The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls ( p = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.

The severity of microstrokes depends on local vascular topology and baseline perfusion

“…As such, it seems plausible that the altered flow field is a possible mechanism by which to affect Aβ deposition and clearance [17] or solute clearance via the perivascular space in general [35]. The local disturbances in the flow field and in solute clearance could build-up and cause additional vessel ruptures [6] or occlusions, which subsequently might further impede clearance [37,57] as well as oxygen and nutrient supply in an increasing area around the MSC. It is important to note that currently the key mechanisms causing the differences in Aβ deposition in response to capillary occlusion are not yet fully understood.…”

“…In recent decades it has become evident that microinfarcts are linked to various pathologies, e.g. cerebral amyloid angiopathy (CAA), cognitive impairment, Alzheimer's disease (AD) and dementia [6][7][8][9][10]. For example, postmortem neuropathological studies revealed that 62% of patients with vascular dementia also suffered from cortical microinfarcts [11].…”

“…Additionally, single capillary occlusion can induce the formation and alter the morphology of amyloid-beta (Aβ) plaques [17], which are related to AD and CAA . Interestingly, Aβ deposits are frequently observed at the core of larger microinfarcts [33,34] and have been associated with blood flow disturbances, which ultimately might lead to microhaemorrhages [6]. Moreover, a higher Aβ prevalence has been shown to negatively affect tissue clearance via the perivascular system [35][36][37] and therewith it might further aggravate the build-up of Aβ deposits.…”

The Expression of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) in Hippocampal Arterioles Declines During Progression of Alzheimer’s Disease

“…2008 ; van Veluw et al. 2016 ) has been recently probed in APP/PS1 mice with CAA ( van Veluw et al. 2020 ).…”

“…2020 ). Although the presence of vascular Aβ deposits in these mice did not directly predispose arterioles in their brains to leak, the physical alterations surrounding the vascular network likely contributed to the formation of spontaneous leakage sites ( van Veluw et al. 2020 ).…”