Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

By R. Bell, E. Winkler, Itender Singh, A. Sagare, R. Deane, Zhenhua Wu, D. Holtzman, C. Betsholtz, A. Armulik, J. Sallstrom and 2 more. Nature, 2012

1,223 citations recorded by the source corpus.

Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer’s disease and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.

Subfields: Hematology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e99d6ac774400b8c05fd2723a8a8e08d1ad5ef0d

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In Hematology

Berislav Zlokovic

In Molecular Biology

In Physiology

Citations in the corpus

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers (2016, methodology): “A further development of this method is in vivo zymography,(114) where substrates are used in a live animal to detect MMP activity in vivo.(115) MMPs in central nervous system disease”
The blood–brain barrier in health and disease: Important unanswered questions (2020, background): “creased TJ proteins and MMP9 elevation along with pericyte degeneration in APOE4 carriers (Bell et al., 2012; Halliday et al., 2016; Nishitsuji et al., 2011).”
From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery (2016, background): “1α,25-dihydroxyvitam D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood–brain barrier.”
The blood-brain barrier in Alzheimer's disease (2017, positive): “…shown that lack of murine Apoe and expression of APOE4 gene, a major genetic risk factor for AD, but not APOE2 and APOE3 , leads to BBB dysfunction by activating a proin ﬂ ammatory cyclophilin A (CypA) – nuclear factor-κ B – matrix-metalloproteinase-9 pathway in mouse pericytes (Bell et al., 2012).”
A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity (2020, background): “Studies in APOE4 transgenic mice suggested that vascular changes may occur early and proceeded by the neuronal behavioral changes [210].”
Blood-Brain Barrier Breakdown in the Aging Human Hippocampus (2015, positive): “PDGFRβ is an established marker of the BBBassociated pericytes (Armulik et al., 2010; Bell et al., 2010, 2012; Winkler et al., 2011 ) that play a key role in maintaining the BBB integrity (Zlokovic, 2008, 2011; Iadecola, 2013; Daneman et al., 2010; Armulik et al., 2010; Bell et al., 2010, 2012;…”
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “flammatory cascades, leading to neurovascular dysfunction, degeneration of the BBB, consequent penetration of toxic proteins from blood into the brain and reduced length of small blood vessels [466].”