Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease

By R. Bell, Berislav Zlokovic. Acta Neuropathologica, 2009

881 citations recorded by the source corpus.

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 β-peptide (Aβ) 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 Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ clearance. Finally, we discuss the role of microglia and perivascular macrophages in Aβ 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.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/3523df5a872401006900d979027d4e895e7e6cf8

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In Neurology

1. M. Pekny
2. M. Sofroniew
3. M. Pekna
4. E. Hol
5. Alexei Verkhratsky
6. J. Attems
7. N. Abbott
8. H. Rosas

In Physiology

1. M. Pekny
2. M. Pekna
3. J. Attems
4. Alexei Verkhratsky
5. E. Hol
6. N. Abbott
7. H. Rosas
8. Siti R. Yusof

Citations in the corpus

• The blood-brain barrier in Alzheimer's disease (2017, neutral): “…to the development of several CNS pathologies, including dementia, thus promoting neurode-generation and cognitive decline during aging and in AD (Deane and Zlokovic, 2007; Lok et al., 2007; Neuwelt et al., 2008; Bell and Zlokovic, 2009; Bell et al., 2010; Zlokovic, 2011; Erickson and Banks, 2013).”
• The overlap between vascular disease and Alzheimer’s disease - lessons from pathology (2014, background): “BBB dysfunctions related to SVD leading to a leakage of plasma proteins into enlarged perivascular spaces [61,128] have been described in WMLs and lacunar stroke [129,130].”
• Structure and function of the blood-brain barrier. (2010, background): “Berzin et al., 2000 Kalaria, 1999 Cirrito et al., 2005 Tai et al., 2009 Zlokovic, 2005 Bell and Zlokovic, 2009 Parkinson's disease Dysfunction of the BBB by reduced efficacy of P-glycoprotein.”
• Age-Associated Reductions in Cerebral Blood Flow Are Independent from Regional Atrophy (2010, background): “, 2010) suggest vascular contributions to Alzheimer's disease (AD) and other dementia (Bell and Zlokovic, 2009; Caroli et al., 2007; de la Torre, 2005; Dickstein et al., 2010; Helzner et al., 2009; Ruitenberg et al., 2005; Sachdev et al., 1999; Zlokovic, 2005).”
• Astrocytes: a central element in neurological diseases (2016, background): “Pathological atrophy of astroglia may also affect the neurovascular unit and reduce coverage of brain vessels with astroglial endfeet, thus contributing to vascular deficits manifest already in the early stages of AD [18, 265].”
• The blood–brain barrier in health and disease: Important unanswered questions (2020, background): “In addition to nonspecific leakage, dysfunction of BBB Aβ transport may drive AD pathology (Bell and Zlokovic, 2009; Erickson and Banks, 2013).”