About the project:
This project, involving the Universities of Southampton (PI: Prof Roxana Carare), Michigan-USA (PI: Prof Scott Counts) and Newcastle (PI: Prof Johannes Attems), will test that degeneration of the locus coeruleus (LC) projection system impairs intramural peri-arterial drainage (IPAD) of amyloid-β (Aβ) peptides from the brain resulting in parenchymal plaques and cerebral amyloidangiopathy (CAA) during Alzheimer’s disease (AD).
Computational modelling shows that innervation of vascular smooth muscle cells provides the motive force for IPAD, which has led us to hypothesize that 1) failure of elimination of Aβ along IPAD pathways could be a major factor in the pathogenesis of AD and 2) LC deafferentation of vascular smooth muscle cells (VSMCs) promotes IPAD failure in AD by impairing the motive force driving this clearance pathway. In support of this hypothesis, pilot studies revealed that treatment of Tg344-19 AD rats with a dopamine-β-hydroxylase IgG-saporin (DBH-SAP) immunotoxin, which resulted in forebrain LC fiber loss and memory impairment, also resulted in increased cortical arteriole wall-to-lumen ratios (a marker of stenosis and reduced vasoreactivity), CAA, and parenchymal albumin extravasation (a marker for blood brain barrier breakdown) when compared to control IgG-saporin (CTL-SAP)-lesioned AD rats. Moreover, pilot human tissue studies suggested that alpha1 adrenoceptor expression is redistributed on VSMCs and endothelial cells in AD occipital cortex, a site of prominent CAA. Furthermore, cholinergic basal forebrain (CBF) degeneration may also impair IPAD function in AD, since CBF neurons innervate VSMCs and lesions using the cholinergic-specific 192-SAP immunotoxin also promotes forebrain CAA accrual. However, the extent to which LC and CBF projection system degeneration impair IPAD and promote toxic amyloidosis, as well as the mechanisms for this phenomenon, are still not known.
To determine whether LC and CBF degeneration impair IPAD individually or synergistically, we will use DBH-SAP and/or 192-SAP and examine Aβ clearance along IPAD pathways in Tg344-19 AD rats. To test whether there is a dysregulation of specific adrenoceptors or cholinergic receptors associated with this effect, which can be explored mechanistically in the future, we will use multi-label quantitative microscopy to evaluate the expression patterns of these receptors in arteriole walls in control and AD/CAA tissue. Hence, this proposal will identify potential vascular targets to enhance IPAD as a therapy for AD/CAA.
Key iDeAC expertise: