Biomimetic Nanocarrier Targeting Drug(s) to Upstream-Receptor Mechanisms in Dementia: Focusing on Linking Pathogenic Cascades

Past published studies have already documented that, subsequent to the intravenous injection of colloidal lipid nanocarriers, apolipoprotein (apo)A-I is adsorbed from the blood onto the nanoparticle surface. The adsorbed apoA-I mediates the interaction of the nanoparticle with scavenger receptors on the blood–brain barrier (BBB), followed by receptor-mediated endocytosis and subsequent transcytosis across the BBB. By incorporating the appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the BBB. Documented similarities in lipid composition between naturally occurring high-density lipoproteins (HDL) and the artificial biomimetic (nanoemulsion) nanocarrier particles can partially simulate or mimic the known heterogeneity (i.e., subpopulations or subspecies) of HDL particles. Such biomedical application of colloidal drug-nanocarriers can potentially be extended to the treatment of complex medical disorders like dementia. The risk factors for dementia trigger widespread inflammation and oxidative stress; these two processes involve pathophysiological cascades which lead to neuronal Ca2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually (late-onset) dementia. In particular, more recent research indicates that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A (SAA)) the release of proinflammatory cytokines. Hence, an effective preventive and therapeutic strategy could be based upon drug targeting toward a major SAA receptor responsible for the SAA-mediated cell signaling events leading to cognitive decline and eventually Alzheimer’s disease or (late-onset) dementia.

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Nanotargeting of Drug(s) for Delaying Dementia: Relevance of Covid-19 Impact on Dementia

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317520976761 ◽

2020 ◽

Vol 35 ◽

pp. 153331752097676

Author(s):

Joseph S. D’Arrigo

Keyword(s):

Risk Factors ◽

Memory Impairment ◽

Late Onset ◽

Scavenger Receptors ◽

Type I ◽

Human Coronavirus ◽

Memory Decline ◽

Class B ◽

Lipid Nanocarriers ◽

Late Onset Dementia

By incorporating appropriate drug(s) into lipid (biobased) nanocarriers, one obtains a combination therapeutic for dementia treatment that targets certain cell-surface scavenger receptors (mainly class B type I, or “SR-BI”) and thereby crosses the blood-brain barrier. The cardiovascular risk factors for dementia trigger widespread inflammation -- which lead to neurodegeneration, gradual cognitive/memory decline, and eventually (late-onset) dementia. Accordingly, one useful strategy to delay dementia could be based upon nanotargeting drug(s), using lipid nanocarriers, toward a major receptor class responsible for inflammation-associated (cytokine-mediated) cell signaling events. At the same time, the immune response and excessive inflammation, commonly observed in the very recent human coronavirus (COVID-19) pandemic, may accelerate the progression of brain inflammatory neurodegeneration—which increases the probability of post-infection memory impairment and accelerating progression of Alzheimer’s disease. Hence, the proposed multitasking combination therapeutic, using a (biobased) lipid nanocarrier, may also display greater effectiveness at different stages of dementia.

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Ovarian cholesterol efflux: ATP-binding cassette transporters and follicular fluid HDL regulate cholesterol content in mouse oocytes†

Biology of Reproduction ◽

10.1093/biolre/ioz159 ◽

2019 ◽

Author(s):

Alonso Quiroz ◽

Paz Molina ◽

Nicolás Santander ◽

Daniel Gallardo ◽

Attilio Rigotti ◽

...

Keyword(s):

Abc Transporters ◽

Follicular Fluid ◽

Scavenger Receptor ◽

Cholesterol Content ◽

Cholesterol Homeostasis ◽

High Density Lipoproteins ◽

Type I ◽

Peripheral Tissues ◽

Knock Out ◽

Class B

Abstract High density lipoproteins (HDL) take up cholesterol from peripheral tissues via ABC transporters and deliver it to the liver via scavenger receptor class B type I (SR-B1). HDL are the main lipoproteins present in follicular fluid (FF). They are thought to derive from plasma, but their origin is still controversial. SR-B1 knock-out (KO) mice have provided important evidence linking HDL metabolism and female fertility. These mice have cholesterol-rich circulating HDL and female infertility that can be restored by treating mice with the cholesterol-lowering drug probucol. Ovulated oocytes from SR-B1 KO females are dysfunctional and show excess cholesterol. The mechanisms explaining the contribution of FF HDL to oocyte cholesterol homeostasis are unknown. Here, using quantitation of filipin fluorescence we show that in SR-B1 KO ovaries, cholesterol excess is first observed in immature oocytes in antral follicles. By performing cross-transplant experiments between WT and apolipoprotein A-I deficient (ApoA-I KO) mice, which lack the main protein component of HDL, we provide evidence supporting the plasmatic origin of FF HDL. Also, we demonstrate that probucol treatment in SR-B1 KO females results in lowering of cholesterol content in their oocytes. Incubation of oocytes from SR-B1 KO mice with purified WT HDL reduces their cholesterol content, suggesting that HDL promote efflux of excess cholesterol from oocytes. In agreement with this hypothesis, we identified ABC transporters in oocytes and observed that ABCA1 KO oocytes have excess cholesterol and lower viability than WT oocytes.

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Induction of Krüppel-like factor 4 by high-density lipoproteins promotes the expression of scavenger receptor class B type I

FEBS Journal ◽

10.1111/j.1742-4658.2010.07779.x ◽

2010 ◽

Vol 277 (18) ◽

pp. 3780-3788 ◽

Cited By ~ 5

Author(s):

Tao Yang ◽

Caihong Chen ◽

Bin Zhang ◽

He Huang ◽

Ganqiu Wu ◽

...

Keyword(s):

Scavenger Receptor ◽

High Density ◽

High Density Lipoproteins ◽

Type I ◽

Scavenger Receptor Class ◽

Class B

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Serum amyloid A is not incorporated into HDL during HDL biogenesis

The Journal of Lipid Research ◽

10.1194/jlr.ra119000329 ◽

2020 ◽

Vol 61 (3) ◽

pp. 328-337 ◽

Cited By ~ 2

Author(s):

Ailing Ji ◽

Xuebing Wang ◽

Victoria P. Noffsinger ◽

Drew Jennings ◽

Maria C. de Beer ◽

...

Keyword(s):

Adenoviral Vector ◽

Serum Amyloid A ◽

Scavenger Receptor ◽

Serum Amyloid ◽

Type I ◽

Primary Hepatocytes ◽

Amyloid A ◽

Scavenger Receptor Class ◽

Class B ◽

Deficient Mice

Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent particles that are distinct from apoA-I-containing particles and that apoA-I lipidation is unaltered when SAA is overexpressed or added to the cells, indicating that SAA is not incorporated into apoA-I-containing HDL during HDL biogenesis. Like apoA-I formation, generation of SAA-containing particles was dependent on ABCA1, but not on scavenger receptor class B type I. Hepatocytes degraded significantly more SAA than apoA-I. Taken together, our results indicate that SAA’s lipidation and metabolism by the liver is independent of apoA-I and that SAA is not incorporated into HDL during HDL biogenesis.

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