Understanding the Pathophysiology of Cerebral Amyloid Angiopathy

Abstract

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.

Keywords: amyloid beta protein; biomarkers; cerebral amyloid angiopathy; dementia; neuroimaging; outcome; pathophysiology; small vessel disease; treatment.

Figure 1

Amyloid precursor protein (APP) is cleaved in the amyloidogenic pathway by β and γ secretases to form amyloid beta (Aβ) Aβ₄₀ and Aβ₄₂ peptides. Aβ₄₀ is the main peptide associated with cerebral amyloid angiopathy. These peptides are transported across the blood brain barrier (BBB) through membrane receptors and transporters (i.e., low density lipoprotein receptor-related protein 1, LRP-1; receptor advanced glycation end products, RAGE; breast cancer resistance protein, BCRP; permeability glycoprotein, P-gp) and degraded by specific enzymes, such as matrix metallopeptidases (MMPs) and apolipoprotein E (apoE). The accumulation of amyloid fibrils in the walls of the small- and medium-calibre leptomeningeal and cortical arteries may result from increased production and impaired transport and degradation of Aβ peptides. This aberrant pathway causes spontaneous intracerebral haemorrhage, cognitive decline and transient focal neurological events (TFNEs; CNS, central nervous system).