Journal Article

Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

Holtzman, David M., Betsholtz, Christer, Sallstrom, Jan, Winkler, Ethan A., Deane, Rashid, Sagare, Abhay P., Wu, Zhenhua, Armulik, Annika, Singh, Itender, Bell, Robert D., Zlokovic, Berislav V., Berk, Bradford C.

2012

Overview

The APOE4-mediated proinflammatory pathway is shown to initiate blood–brain barrier breakdown and resulting neurodegeneration in transgenic mice. Restoring the blood–brain barrier There are known connections between the Alzheimer's-disease-linked APOE4 gene and cerebrovascular integrity. However, the mechanisms that drive known blood–brain-barrier dysfunction both in rodent models and in APOE4-associated neurological disorders are unknown. Here, Berislav Zlokovic and colleagues report that APOE4 activates a matrix metalloproteinase pathway in cells forming the blood–brain barrier in mice, leading to its breakdown and the neuronal uptake of blood-derived neurotoxic proteins. In turn, microvascular and cerebral blood flow are reduced; together, these deficits can initiate neurodegenerative changes in rodents. The authors suggest that cyclophilin A (CypA), a component of the APOE4-activated pathway, is a potential target for treating APOE4-mediated neuronal dysfunction. Treatment with the CypA inhibitor cyclosporine A restores the blood–brain barrier in APOE4 mice. Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4 1 . APOE4 is a major genetic risk factor for Alzheimer’s disease 2 , 3 and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage 3 . Neurovascular dysfunction is present in normal APOE4 carriers 4 , 5 , 6 and individuals with APOE4 -associated disorders 3 , 7 , 8 , 9 , 10 . In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown 11 , 12 , whereas APOE4 increases BBB susceptibility to injury 13 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/340 / 631/443/592/75/593/1370 / 631/45/612/1191 / 692/699/375/365/1283 / Adult and adolescent clinical studies / Alzheimer's disease / Animals / Apolipoprotein E2 - deficiency / Apolipoprotein E2 - genetics / Apolipoprotein E2 - metabolism / Apolipoprotein E3 - deficiency / Apolipoprotein E3 - genetics / Apolipoprotein E3 - metabolism / Apolipoprotein E4 - deficiency / Apolipoprotein E4 - genetics / Apolipoprotein E4 - metabolism / Apolipoproteins / Apolipoproteins E - deficiency / Apolipoproteins E - genetics / Apolipoproteins E - metabolism / Biological and medical sciences / Blood-Brain Barrier - drug effects / Blood-Brain Barrier - physiology / Blood-Brain Barrier - physiopathology / Brain cells / Cerebrovascular Circulation - physiology / Cyclophilin / Cyclophilin A - antagonists & inhibitors / Cyclophilin A - deficiency / Cyclophilin A - metabolism / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Development and progression / Hippocampus - metabolism / Hippocampus - pathology / Humanities and Social Sciences / Humans / letter / Matrix Metalloproteinase 9 - metabolism / Medical sciences / Mice / Mice, Transgenic / Microcirculation / multidisciplinary / Neurodegenerative Diseases - metabolism / Neurodegenerative Diseases - pathology / Neurology / Neurons - metabolism / Neurons - pathology / NF-kappa B - metabolism / Organic mental disorders. Neuropsychology / Pericytes - metabolism / Physiological aspects / Properties / Proteins / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Rodents / Science / Studies