Transcriptional and post-transcriptional responses to amyloid- β in cerebral amyloid angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease characterized by amyloid-beta (Aβ) accumulation in cortical and leptomeningeal blood vessel walls. Reduced Aβ clearance in the vasculature elevates the risk of CAA, while increasing evidence indicates that enhanced Aβ production in neurons also contributes. The impact of Aβ on the diverse cell types of the neurovascular unit (NVU)-including endothelial cells (ECs), pericytes, neurons, vascular smooth muscle cells (VSMCs), and astrocytes-remains unclear. This narrative review proposes that Aβ accumulation in NVUs during CAA drives a transcriptional response that reduces Aβ clearance while activating a neuron-specific post- transcriptional response that enhances Aβ production. Specifically, Aβ in NVUs was found to initiate a transcriptional cascade that destabilizes endothelial cells, increases blood-brain barrier permeability, and damages pericytes, ultimately inducing inflammatory and dysfunctional changes in VSMCs. These changes cause mitochondrial dysfunction and TGFβ deregulation in neurons, activating profibrotic mechanisms. Post-transcriptional regulation by microRNA networks in neurons affects Aβ processing by controlling the balance between amyloidogenic and non-amyloidogenic pathways through BACE1 and ADAM10 expression respectively. This review improves our understanding of Aβ accumulation in neurovascular units in CAA, potentially leading to better diagnostics, early biomarkers, and tools for prognosis and treatment.

Keywords: Cerebral amyloid angiopathy; amyloid-beta; microRNA; neurovascular unit; transcripts.

Figure 1.

Segmental variation of the neurovascular unit. (a) In arteries, endothelial cells are surrounded by multiple layers of VSMCs and astrocytic end-feet, which support neurovascular coupling and maintain the integrity of the blood-brain barrier. (b) Larger arterioles have a single layer of VSMCs. Here the basement membranes of endothelial cells and VSMCs fuse but remain separated from the astrocytic basement membrane by the perivascular space. (c) In smaller arterioles, the vascular basement membrane merges with the astrocytic end-feet basement membrane, resulting in the loss of the perivascular space and (d) In capillaries, pericytes together with endothelial cells form the capillary wall and regulate cerebral blood flow.

Figure 2.

Transcriptional response to amyloid-β in neurovascular units in cerebral amyloid angiopathy. (a) In arteries, CAA is characterized by increased reactive astrocytes surrounding remodeled vessels and prominent concentric splitting of the vessel wall. (b) Early CAA formation is characterized by Aβ accumulation at the larger pial surface arterioles that follows the banding pattern of vascular smooth muscle cells, eventually reaching a confluent circumferential appearance. (c) In arterioles, Aβ is initially deposited within the outer basement membranes surrounding intact smooth muscle cells, sparing the basement membranes of the endothelium and (d) In capillaries, Aβ accumulation in the tunica intima (dark red line) disrupts endothelial quiescence, triggering reactive oxygen species (ROS) production and morphological damaged pericytes. Consequently, Aβ promotes capillary rarefaction, leading to irregular capillary growth with reduced pericyte coverage.

Figure 3.

Post-transcriptional responses to amyloid-β in neurovascular units in cerebral amyloid angiopathy. Left panel depicts that loss of microRNA function in neurons promotes the amyloidogenic pathway by disrupting BACE1 inhibition. Right panel indicates that gain of microRNA function in neurons suppresses ADAM10 expression, thereby inactivating the non-amyloidogenic pathway and resulting in elevated Aβ production.