Intrahippocampally Injected Human Recombinant Clusterin Reduces Amyloid-β Aggregate Size in Cerebral Arteriole Walls of Clusterin Knockout Mice

Abstract

Aims: The clusterin (CLU) gene is genetically associated with Alzheimer's disease (AD), and CLU levels have been shown to positively correlate with regional Aβ deposition in the brain, including in arteries from cerebral amyloid angiopathy (CAA) patients. CLU has also been shown to alter the aggregation, toxicity and blood-brain barrier transport of amyloid beta (Aβ) and has therefore been suggested to play a key role in regulating the balance between Aβ deposition and clearance in both the brain and cerebral blood vessels. However, it remains unclear whether the role of clusterin in relation to Aβ deposition is protective or pathogenic. The aim of this study was to determine how the presence of clusterin influences the pattern of Aβ deposition in hippocampal cerebral vessels.

Methods: Intrahippocampal injections of fluorescent human recombinant Aβ alone or in combination with human recombinant CLU were carried out in Clu knockout mice. Aβ deposition and aggregate size in arterioles and capillaries were assessed by confocal microscopy.

Results: The presence of CLU significantly reduced the size of Aβ deposits in the walls of cerebral arterioles but not in the tissue outside arterioles. There was no significant difference in overall Aβ deposition within cerebral arterioles and capillaries of mice injected with Aβ + CLU versus Aβ alone.

Conclusions: Our findings confirm that CLU directly impacts cerebral vascular Aβ aggregation, the implications of which are particularly relevant to CAA, which is a major cause of cerebral haemorrhage and cognitive decline, particularly in individuals with AD.

Keywords: amyloid beta (Aβ); clusterin; confocal microscopy; intramural periarterial drainage.