Abstract
Cerebrovascular homeostasis is maintained by the blood-brain barrier (BBB), a highly selective structure that separates the peripheral blood circulation from the brain and protects the central nervous system (CNS). Dysregulation of BBB function is the precursor of several neurodegenerative diseases including Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), both related to β-amyloid (Aβ) accumulation and deposition. The origin of BBB dysfunction before and/or during CAA and AD onset is not known. Several studies raise the possibility that vascular dysfunction could be an early step in these diseases and could even precede significant Aβ deposition. Though accumulation of neuron-derived Aβ peptides is considered the primary influence driving AD and CAA pathogenesis, recent studies highlighted the importance of the physiological role of the β-amyloid precursor protein (APP) in endothelial cell homeostasis, suggesting a potential role of this protein in maintaining vascular stability. In this review, we will discuss the physiological function of APP and its cleavage products in the vascular endothelium. We further suggest how loss of APP homeostatic regulation in the brain vasculature could lead toward pathological outcomes in neurodegenerative disorders.
Highlights
The brain vasculature is characterized by the presence of the blood-brain barrier (BBB), a specialized structure that maintains the separation between the circulating blood and central nervous system (CNS)
The latter leads to the release in the extracellular space of the soluble form soluble amyloid precursor protein generated by α-secretase (ADAM10) cleavage and the p3 peptide through cleavage of α-secretase and the γ-secretase complex
Even if amyloid precursor protein (APP) is notoriously known for its contribution to pathogenesis of neurodegenerative diseases, and many physiological roles have been identified in neural cells (Perez et al, 1997; Nicolas and Hassan, 2014; Nhan et al, 2015; Habib et al, 2017; Coronel et al, 2018), little is known on its function on endothelial cells and cerebral vasculature (Figure 2)
Summary
The brain vasculature is characterized by the presence of the blood-brain barrier (BBB), a specialized structure that maintains the separation between the circulating blood and central nervous system (CNS). The BBB is an essential part of the neurovascular unit (NVU), defined as a complex functional and anatomical structure composed of BBB endothelium, basement membranes (basal lamina and extracellular membranes), astrocytes, pericytes, microglial cells, and neurons In this context, the neuronal-vascular interaction is critical for proper brain function, and the structural and functional integrity of blood vessels is essential to maintain appropriate brain perfusion and to preserve normal neurological function. Immunotherapy with bapineuzumab, a monoclonal antibody targeting both fibrillar and soluble Aβ, showed severe vascular adverse events like brain vasogenic edema and microhemorrhages, possibly due to a loss in cerebrovascular integrity (Gustafsson et al, 2018) This suggests that physiological levels of Aβ are necessary for normal vascular homeostasis. We summarize these findings and highlight the importance of APP and its metabolites on the normal physiology of the vascular system
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