Intravenously Injected Human Apolipoprotein A‐I Rapidly Enters the Central Nervous System via the Choroid Plexus

Stukas, Sophie; Robert, Jérôme; Lee, Michael; Kulic, Iva; Carr, Michael; Tourigny, Katherine; Fan, Jianjia; Namjoshi, Dhananjay; Lemke, Kalistyne; DeValle, Nicole; Chan, Jeniffer; Wilson, Tammy L.; Wilkinson, Anna; Chapanian, Rafi; Kizhakkedathu, Jayachandran N.; Cirrito, John R.; Oda, Michael N.; Wellington, Cheryl L.

doi:10.1161/jaha.114.001156

Cited by 83 publications

(97 citation statements)

References 59 publications

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“…By contrast, as apoA-I is produced only in liver and intestine, HDL is found in the circulation and would affect cerebrovascular function from the lumen. Although lipid-free apoA-I can be transported into the brain and is present in CSF (Stukas et al, 2014a), there is thus far no evidence that mature HDL might cross the BBB. Our results support a functional cooperation between brain apoE and circulating HDL to promote clearance of Ab through the cerebral vessel by mechanisms that remain to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Robert

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Soo

et al. 2017

Alzheimer's & Dementia

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Amyloid plaques, consisting of deposited beta-amyloid (Ab), are a neuropathological hallmark of Alzheimer's Disease (AD). Cerebral vessels play a major role in AD, as Ab is cleared from the brain by pathways involving the cerebrovasculature, most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-dimensioinal model of CAA in bioengineered human vessels. We show that lipoproteins including brain (apoE) and circulating (high-density lipoprotein, HDL) synergize to facilitate Ab transport across bioengineered human cerebral vessels. These lipoproteins facilitate Ab42 transport more efficiently than Ab40, consistent with Ab40 being the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Ab transport, also consistent with the well-established role of apoE4 in Ab deposition in AD.

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Section: Discussionmentioning

confidence: 99%

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Robert

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Soo

et al. 2017

Alzheimer's & Dementia

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“…Intravenously injected recombinant, fluorescently labeled human apoAI rapidly appears in CSF. 35 ApoAI is primarily transferred in the choroid plexus. Cultured primary human choroid plexus epithelial cells bind, internalize, and transfer apoAI across the cells.…”

Section: Lipoprotein Synthesis and Metabolism In The Cns In Humansmentioning

confidence: 99%

“…Although the choroid plexus contains numerous specific transporters, the apoAI transporter is not known. 35 …”

Section: Lipoprotein Synthesis and Metabolism In The Cns In Humansmentioning

confidence: 99%

Central Nervous System Lipoproteins

Mahley

2016

ATVB

363

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ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease.

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“…ApoA-I, though not synthesized in the brain, is present in the central nervous system (CNS), due to its ability to cross the blood brain barrier (BBB) from the periphery [19, 20]. In view of the important role of apoA-I in lipid transport in the periphery, it is presumed that apoA-I plays a similar role in the brain [20–22]. Clusterin (apoJ) is another major apolipoprotein in the brain.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins

et al. 2016

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Apolipoprotein E4 (apoE4), the leading genetic risk factor for Alzheimer's disease (AD), is less lipidated compared to the most common and AD-benign allele, apoE3. We have recently shown that i.p. injections of the ATP-binding cassette A1 (ABCA1) agonist peptide CS-6253 to apoE mice reverse the hypolipidation of apoE4 and the associated brain pathology and behavioral deficits. While in the brain apoE is the main cholesterol transporter, in the periphery apoE and apoA-I both serve as the major cholesterol transporters. We presently investigated the extent to which apoE genotype and CS-6253 treatment to apoE3 and apoE4-targeted replacement mice affects the plasma levels and lipid particle distribution of apoE, and those of plasma and brain apoA-I and apoJ. This revealed that plasma levels of apoE4 were lower and eluted faster following FPLC than plasma apoE3. Treatment with CS-6253 increased the levels of plasma apoE4 and rendered the elution profile of apoE4 similar to that of apoE3. Similarly, the levels of plasma apoA-I were lower in the apoE4 mice compared to apoE3 mice, and this effect was partially reversed by CS-6253. Conversely, the levels of apoA-I in the brain which were higher in the apoE4 mice, were unaffected by CS-6253. The plasma levels of apoJ were higher in apoE4 mice than apoE3 mice and this effect was abolished by CS-6253. Similar but less pronounced effects were obtained in the brain. In conclusion, these results suggest that apoE4 affects the levels of apoA-I and apoJ and that the anti-apoE4 beneficial effects of CS-6253 may be related to both central and peripheral mechanisms.

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Intravenously Injected Human Apolipoprotein A‐I Rapidly Enters the Central Nervous System via the Choroid Plexus

Cited by 83 publications

References 59 publications

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

Central Nervous System Lipoproteins

Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins

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