Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease

Abstract

Vascular dysfunction has a critical role in Alzheimer's disease (AD). Recent data from brain imaging studies in humans and animal models suggest that cerebrovascular dysfunction may precede cognitive decline and onset of neurodegenerative changes in AD and AD models. Cerebral hypoperfusion and impaired amyloid beta-peptide (Abeta) clearance across the blood-brain barrier (BBB) may contribute to the onset and progression of dementia AD type. Decreased cerebral blood flow (CBF) negatively affects the synthesis of proteins required for memory and learning, and may eventually lead to neuritic injury and neuronal death. Impaired clearance of Abeta from the brain by the cells of the neurovascular unit may lead to its accumulation on blood vessels and in brain parenchyma. The accumulation of Abeta on the cerebral blood vessels, known as cerebral amyloid angiopathy (CAA), is associated with cognitive decline and is one of the hallmarks of AD pathology. CAA can severely disrupt the integrity of the blood vessel wall resulting in micro or macro intracerebral bleedings that exacerbates neurodegenerative process and inflammatory response and may lead to hemorrhagic stroke, respectively. Here, we review the role of the neurovascular unit and molecular mechanisms in vascular cells behind AD and CAA pathogenesis. First, we discuss apparent vascular changes, including the cerebral hypoperfusion and vascular degeneration that contribute to different stages of the disease process in AD individuals. We next discuss the role of the low-density lipoprotein receptor related protein-1 (LRP), a key Abeta clearance receptor at the BBB and along the cerebrovascular system, whose expression is suppressed early in AD. We also discuss how brain-derived apolipoprotein E isoforms may influence Abeta clearance across the BBB. We then review the role of two interacting transcription factors, myocardin and serum response factor, in cerebral vascular cells in controlling CBF responses and LRP-mediated Abeta clearance. Finally, we discuss the role of microglia and perivascular macrophages in Abeta clearance from the brain. The data reviewed here support an essential role of neurovascular and BBB mechanisms in contributing to both, onset and progression of AD.

Fig. 1

Cerebral amyloid angiopathy in AD. Immunofluorescent staining of smooth muscle α actin (SMA; red) and amyloid staining (thioflavin S, green) in an AD cerebral vessel from Brodmann area 9. Staining shows significant amyloid accumulation in the vascular smooth muscle cell (VSMC) layer of this blood vessel. Amyloid accumulation may result from decreased Aβ clearance along the perivascular spaces caused by a decreased low-density lipoprotein receptor related protein-1 (LRP)-mediated Aβ clearance by VSMC, faulty Aβ clearance by perivascular macrophages and/or reduced passive Aβ drainage due to reductions in the arterial pulsatile blood flow. CAA can lead to spontaneous hemorrhage and rupture of the vessel wall due to a loss of the VSMC layer, enzymatically-induced breakdown of the vessel wall, oxidant stress and cytokine-mediated vascular injury. Scale bar 25 µm

Fig. 2

Essential Aβ clearance vascular and other routes. Aβ clearance can occur via several routes: 1 LRP-mediated transcytosis (purple, receptor) across the blood–brain barrier (red, capillaries) removes Aβ from brain interstitial fluid to blood and LRP-mediated degradation of Aβ on vascular smooth muscle cells and pericytes lowers Aβ levels in perivascular spaces (blue, cells), 2 soluble LRP, sLRP-mediated (purple, soluble receptor) endogenous Aβ “sink” action in plasma increases peripheral Aβ clearance and lowers the levels of free Aβ in the circulation which in turn promotes the cell surface LRP-mediated clearance of brain-derived Aβ across the blood–brain barrier, 3 Aβ chaperones in brain interstitial fluid such as ApoE isoforms may reduce clearance of brain-derived Aβ in an isoform-specific manner, i.e., apoE4 > apoE3 or apoE2, 4 clearance of Aβ by microglia and perivascular brain macrophages (orange, cells) from brain parenchyma and perivascular spaces, respectively, 5 direct enzymatic degradation of Aβ in the brain (green, enzymes), and 6 elimination of Aβ along the perivascular spaces by passive drainage that is influenced by the arterial pulstatile flow. The illustrated pathways by all means do not cover in detail all possible routes that control Aβ levels in the brain

Fig. 3

MYOCD and SRF hypothesis of AD arterial pathology. High levels of SRF-MYOCD in AD VSMC contribute to brain hypoperfusion (white pathway) by increasing the expression of contractile proteins, such as smooth muscle (SM) α-actin, calponin, and myosin heavy chain (MHC) and by increasing the expression of genes that regulate calcium homeostasis. This leads to arterial hypercontractility, reduced resting cerebral blood flow (CBF) and attenuated CBF responses to brain activation, which ultimately creates a chronic hypoperfusion state. Furthermore, SRF-MYOCD potentiate CAA and focal brain Aβ accumulation (yellow pathway) via CArG-box dependent activation of SREBP2, which acts as transcriptional suppressor of LRP, a key Aβ clearance receptor