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

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.