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.
Highlights
Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid fibrils in the walls of small to medium-sized arterial blood vessels, and in capillaries of the central nervous system (CNS) parenchyma and leptomeninges, is a major cause of spontaneous intracerebral haemorrhage (ICH) in elderly people and an important contributor to age-related cognitive decline
Robert J. and colleagues demonstrated that the anti-CAA and anti-inflammatory functions of HDL are mediated by distinct mechanisms, and they defined four distinct pathways that HDL uses to attenuate Aβ accumulation, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) diminishing collagen-I protein levels produced by smooth muscle cells (SMCs), and iv) attenuating Aβ uptake into SMCs that is associated with reduced low density lipoprotein receptor-related protein 1 (LRP-1) levels [89]
Since Aβ peptides can be degraded by proteolytic enzyme or be cleared via perivascular spaces by blood-brain barrier (BBB) or lymphatic system, the impairment of one or more of these mechanisms can induce the disease by Aβ deposition in the basement membranes of small vessel disease
Summary
Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid fibrils in the walls of small to medium-sized arterial blood vessels, and in capillaries of the central nervous system (CNS) parenchyma and leptomeninges, is a major cause of spontaneous intracerebral haemorrhage (ICH) in elderly people and an important contributor to age-related cognitive decline. The disease diagnostic confirmation is pathological, several neuroradiological features including lobar cerebral microbleeds, cortical superficial siderosis, cortical microinfarcts, white matter hyperintensities and enlarged peri-vascular spaces in semioval centres have been identified as possible disease features [1]. Of these lobar intracerebral haemorrhage, lobar microbleeds, and cortical superficial siderosis are considered so far the only disease biomarkers and are mandatory for CAA clinical diagnosis, according to the Boston modified criteria [2,3], some serological and cerebrospinal fluid (CSF) biomarkers such as Aβ42 and Aβ40 levels have been proposed for diagnostic purposes with controversial results [4,5]. The aim of the present review is to discuss the key disease pathophysiological mechanisms and experimental models and dissect their relevance for understanding CAA and for the design of future research studies
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