Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

Abstract

Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE41. APOE4 is a major genetic risk factor for Alzheimer’s disease2, 3 and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage3. Neurovascular dysfunction is present in normal APOE4 carriers4, 5, 6 and individuals withAPOE4-associated disorders3, 7, 8, 9, 10. In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown11, 12, whereas APOE4 increases BBB susceptibility to injury13. 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.

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

“…Amyloid‐dependent theories make use of the fact that ApoE, either by direct binding to Aβ 42 or by competition with Aβ receptors, such as the lipoprotein receptor‐related protein‐1 43, is able to modify Aβ production 44 or clearance 45. Amyloid‐independent theories implicate the cytotoxicity of ApoE4 fragments 46, its role in cholesterol homeostasis 35, neuroprotection/apoptosis 20, neurite outgrowth 19, inflammation 47, and vascular integrity 48. AD is clearly a multifaceted disease, with changes in amyloid metabolism occurring alongside these amyloid‐unrelated phenomena.…”

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

“…ApoE appears to protect cerebrovascular integrity in acute brain injury through maintenance of the BBB, as demonstrated in apoE‐deficient mice, which was associated with an increase in disruption of BBB after injury 67, 68, 69. More recently, it has been found that apoE stabilizes BBB through suppression of cyclophilin A (Peptidylprolyl cis‐trans isomerase A or CypA) in an isoform‐specific manner via interaction with LRP1 57. We observed, through our phosphoproteomic study, that CN‐105 downregulated phosphorylation of CypA in ischemic stroke.…”

“…LRP1, a cell surface receptor, has been shown to bind apoE55 and other apoE‐mimetic peptides 29, 56. The function of this interaction between apoE and LRP1, has been associated with suppression of neuroinflammation 57. Microglial cells, which expresses LRP1, are resident macrophages within the CNS that become activated in pathological situations, including cerebral ischemia 58.…”

Apolipoprotein E epsilon 4 (APOE‐ε4) genotype is associated with decreased 6‐month verbal memory performance after mild traumatic brain injury

“…Our analysis replicates this phenomenon, as CT pathology was the driver of decreased cognitive performance following mTBI, with greater deleterious associations with consolidation and retrieval rather than encoding. This supports the idea that following ischemia and neuronal damage, the reduced antioxidant and biological activity of the ε 4 allele may exacerbate vascular endothelial injury (Bell et al., 2012; Halliday et al., 2016) and lead to cognitive deficits (Friedman et al., 1999). Similar results have been described in AD patients with left temporal and/or hippocampal damage, where a subtle decline in episodic memory occurs prior to the emergence of full dementia.…”