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Nano Progress
Review Article
Nanotargeting Dementia Etiology: Aiming Drug Nanocarriers Toward Receptors for Vascular Endothelium, Serum Amyloid A, Inflammasomes, and Oxidative Stress
Joseph S. D'Arrigo
Cavitation-Control Technology Inc., Farmington, CT 06032, USA
1 Present address: Cav-Con Inc., Bellevue, WA 98007, USA
*Corresponding author E-mail address: cavcon@ntplx.net (Joseph S. D'Arrigo)
Abstract: Much evidence has been published which indicates that microvascular endothelial dysfunction, due to cerebrovascular risk factors (e.g., atherosclerosis, hypertension, obesity, diabetes, smoking, aging), precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis. By incorporating 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 blood-brain barrier (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 cardiovascular risk factors for dementia trigger widespread inflammation and oxidative stress; these two interacting processes involve pathophysiological cascades which lead to neuronal Ca2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually (late-onset) dementia. In particular, recent research indicates that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A (SAA)) the release of proinflammatory cytokines. At the same time, increased BBB permeability due to aging (or dysfunction), in turn, allows these proinflammatory cytokines to enter the brain, inducing glia reactivity. These recent findings, and various past studies, indicate that inflammation plays an important role in the process of Aβ deposition and, therefore, the inhibition of inflammatory cascades may attenuate amyloidogenic processes—such as Alzheimer's disease. Hence, an effective preventive and therapeutic strategy could be based upon nanotargeting drug(s), using lipid nanocarriers, toward a major SAA receptor responsible for numerous SAA-mediated cell signaling events leading to cognitive decline and eventually Alzheimer's disease or (late-onset) dementia.
Keywords: Alzheimer's disease; dementia; drug nanotargeting; inflammasome; nanocarrier; oxidative stress; serum amyloid A
Publication details: Received: 29th May 2020; Revised: 19th June 2020; Accepted: 22nd June 2020; Published: 29th June 2020
1. Introduction
A fundamental involvement of the cerebrovasculature in the pathogenesis of common dementias is widely reported in the biomedical literature (see[1,2] for reviews). Such published studies indicate that microvascular endothelial dysfunction precedes, often by decades, the cognitive decline associated with Alzheimer's disease (e.g.,[3]). Hence, preservation of a healthy cerebrovascular endothelium can be an important therapeutic target.
2. Endothelial Dysfunction as a Therapeutic Target for Cognitive Impairment
It has been reported repeatedly that endothelial modulation and repair is feasible by pharmacological targeting[1,2,4-10] of the SR-BI receptors (i.e., “scavenger receptor class B, type I”).[10,11] Recently, Fung et al.[12] specifically found that SR-BI mediates the uptake and transcytosis of high-density lipoproteins (HDL) across brain microvascular endothelial cells (i.e., across the BBB). These investigators further argue that manipulation of HDL transcytosis across the BBB to increase delivery of plasma apoA-I may, in turn, facilitate increasing the transport of “HDL-like synthetic particles” containing therapeutic drug across the BBB to treat neurodegenerative disorders such as Alzheimer's disease.[12] Since SR-BI has already been identified as a major receptor for HDL (with their major apolipoprotein (apo)A-I) as well as for the recently reviewed[1,2] “lipid-coated microbubble/nanoparticle-derived” (LCM/ND) nanoemulsion (see below), this multitasking lipid nanoemulsion can arguably serve as a targeted, apoA-I-based, (SR-BI mediated) therapeutic agent for common (late-onset) dementias.[13-15]
This targeted (LCM/ND-delivery) type approach receives added impetus from continual findings of cerebrovascular pathology[1,16-26] and an apparent endothelium dysfunction[2,15,19,22,27-33] in both Alzheimer's disease and its major risk factors.[1,2,26-38] By incorporating drug molecules into the LCM/ND lipid nanoemulsion type (yielding particle sizes mostly < 0.1 μm in diameter - see Fig. 1), known to be a successful drug carrier,[39,40] one is likely to obtain a multitasking combination therapeutic capable of targeting cell-surface SR-BI. This (intravenous) combination therapeutic would make it possible for various cell types, all potentially implicated in Alzheimer's disease,[1,2] to be simultaneously sought out and better reached for localized drug treatment of brain tissue in vivo.[39,40]
![](/webadmin/ckeditor_html/kcfinder/upload/images/Ariviyal.NP.2020.02.03.011/Fig.%201.jpg)
3. LCM/ND Nanoemulsion Type, and Targeting via Lipid Cubic Phases
Documented similarities in lipid composition, between naturally occurring high-density lipoproteins (HDL) and the artificial biomimetic nanocarrier particles (i.e., the LCM/ND nanoemulsion type), can partially simulate or mimic the known heterogeneity (i.e., subpopulations or subspecies) of HDL particles (see[39] for a review). Moreover, the above-described type BI scavenger receptor (i.e., either SR-BI (rodent) and/or CLA-1 (human) orthologs) has been shown to be a multifunctional receptor able to bind a broad variety of ligands. The presence of amphipathic helices is a common feature of “exchangeable apolipoproteins”, which are known to be the primary ligands (including notably apoA-I) for SR-BI.[39]
As concerns the specific lipid composition of this LCM/ND nanoemulsion type, monoglycerides are known to exhibit different phase behaviors when they are exposed to water.[41-48] Of special interest, the dispersed Fd3m cubic phase can represent a lipid/water system which is particularly relevant to the earlier-described (Filmix®) LCM/ND lipid nanoemulsion formulation(s) on account of the fact that the patent claims describing the precise lipid composition of such nanoemulsion formulations (see especially Claim #1 in[49]) specifically include cholesterol and three categories of (saturated) glycerides, that is, tri-, di-, and monoglycerides.[49] In view of the advantageous attributes of monoglycerides (alluded to above), and since (saturated) monoglyceride represents the largest single-lipid fraction of the LCM/ND lipid nanoemulsion type, the monoglyceride content probably plays a dominant role in supporting the evident long-term stability of the liquid-crystalline lipid nanoparticles in such nanoemulsions.[39]
In this particular targeted-delivery approach, the self-assembled “lipid particle” structure itself (after intravenous injection) is directed via (adsorption of) plasma lipoproteins, including notably apoA-I, toward the appropriate endocytic receptors on the target-cell surface.[39]
4. Cardiovascular Risk Factors, Inflammation, Serum Amyloid A (SAA), Oxidative Stress, and SR-BI
The cardiovascular risk factors for dementia induce brain tissue hypoxia, leading to endothelial cell activation. The result is the production/release of reactive oxygen species (ROS) and proinflammatory proteins, which together trigger widespread inflammation and oxidative stress—both of which can lead to BBB disruption.[50] (Note that inflammation is intimately associated with oxidative stress in Alzheimer's disease. The redox status modulates inflammatory factors involvement in signaling processes, which are critical mediators of oxidative stress and neuroinflammation, causing neurodegeneration. The resultant cellular damage promotes further neuroinflammation in the Alzheimer's-disease brain.[51]) These pathological cascades lead to a neuronal Ca2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually Alzheimer's disease.[3]
While the risk factors for dementia trigger widespread inflammation and oxidative stress (e.g.,[3]), it is also true that these two processes can result in more biological effects than enhanced calcium load in brain tissue and neurodegeneration (cf.[52]). In fact, oxidative stress and inflammation each involve pathophysiological cascades associated with a wide range of pathologies and especially aging. However, these two processes/cascades are not always associated with biological damage. (For example, oxidative stress constitutes an important mechanism in many physiological processes, such as adaptations to physical exercise and cell signaling.) Yet, when oxidative stress and/or inflammation are dysregulated, their action is harmful.[52] (In this situation, one corresponding example [of many] occurs in Alzheimer's disease, where growing evidence links the ROS-mediated damages with molecular targets including mitochondrial dynamics/function, autophagic pathways, and proteostasis balance.[53]) Accordingly, Khalil et al.[54] found that Alzheimer's disease impaired the interaction of HDL (and ApoA-I) with the SR-BI receptor, and their experimental results indicated that such patients had higher levels of oxidative stress.[54] The authors concluded that their clinical study provides evidence for the first time that the functionality of HDL is impaired in Alzheimer's disease, and that this alteration may be caused by Alzheimer's disease-associated oxidative stress and inflammation.[54] This conclusion is consistent with earlier work where SR-BI was identified on astrocytes and vascular smooth muscle cells in Alzheimer's disease brain, and has been demonstrated to mediate the adhesion of microglia to aggregated Aβ (cf.[55]). Moreover, these authors further report that SR-BI mediates perivascular macrophage response, and regulates Aβ-related pathology and cerebral amyloid angiopathy, in an Alzheimer's-disease mouse model.[55] Fig. 2 shows SR-BI reduction increases vascular and hippocampal fibrillar amyloid deposition in the mouse brain.
![](/webadmin/ckeditor_html/kcfinder/upload/images/Ariviyal.NP.2020.02.03.011/Fig%202.png)
5. Inflammasomes, Gut-Brain Axis, SAA versus SR-BI Targeting, and Cognitive Impairment
Systemic inflammation is well known to increase the risk for cognitive decline in human neurodegenerative disorders including Alzheimer's disease. This belief is based on wide acceptance that several factors including obesity, acute injuries, aging, and neurodegenerative disease can trigger a sustained immune response in the central nervous system (CNS) leading to neuronal dysfunction and destruction by microglia activation and release of neuroinflammatory mediators (e.g.,[56]). Initiation of the inflammatory response by microglia involves the intracellular multiprotein complexes termed “inflammasomes” (e.g.,[56-58]). The “NLRP3 inflammasome” has become the most studied inflammasome, over recent years, due to its activation by a diverse range of stimuli and contribution to the pathology of inflammatory diseases.[59-63] More specifically, NLRP3 inflammasome activation has been implicated in the pathogenesis of neurodegenerative diseases, especially Alzheimer's disease; various findings suggest that NLRP3 inflammasome activation, induced by Aβ, promotes the pathogenesis of Alzheimer's disease by triggering the release of proinflammatory cytokines and neuroinflammation[59] However, animal model studies demonstrate that HDL protects against memory deficits, neuroinflammation, and cerebral amyloid angiopathy; recently, in vitro studies confirm that HDL reduces vascular Aβ accumulation and attenuates Aβ-induced endothelial inflammation.[64] Correspondingly, in cellular experiments where the NLRP3 inflammasome was inhibited, it has been reported that an upregulation of SR-BI receptor expression was observed (but there was no effect on the expression of scavenger receptor class A).[65] Since SR-BI is known to act as a receptor for both HDL/apoA-I and SAA [see below], it is consistent that SAA is detected in Alzheimer's-disease brain and this finding supports a linking of SAA with CNS pathophysiology.[66] Lastly, cerebrovascular disease is a common co-morbidity in patients with Alzheimer's disease, and is believed to contribute additively to the cognitive impairment as well as lower the threshold for developing dementia. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its associated mediators interact synergistically. In Alzheimer's disease, the cerebral vasculature is the location where multiple pathogenic processes converge and contribute to cognitive impairment. When inflammatory cytokines and chemokines reach the brain parenchyma, they can be neurotoxic, and spur local inflammation by activation of glia. In addition, this activation of glia cells can increase Aβ secretion and cleavage. Exposure of endothelial cells to Aβ will itself, in turn, promote the release of a large variety of inflammatory mediators.[67]
Particularly noteworthy is more recent research[68,69] indicating that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A (SAA)) the release of proinflammatory cytokines. At the same time, increased BBB permeability due to aging (or dysfunction), in turn, allows these proinflammatory cytokines to enter the brain, inducing glia reactivity.[68,69] These recent findings and various past studies indicate that inflammation plays an important role in the process of Aβ deposition and, therefore, the inhibition of inflammatory cascades may attenuate amyloidogenic processes—such as Alzheimer's disease[70] (cf.[54,71]). Hence, an effective preventive and therapeutic strategy could be based upon nanotargeting drug(s) toward a major SAA receptor responsible for numerous SAA-mediated cell signaling events leading to cognitive decline and eventually Alzheimer's disease or (late-onset) dementia.
Specifically, earlier research[72] has already confirmed that SR-BI receptors (or its human ortholog CLA-1) function as cell-surface SAA receptors—which bind, internalize, and mediate SAA-induced proinflammatory effects (cf.[73]). However, Baranova et al. additionally report that (in cell culture) CLA-1/SR-BI ligands “efficiently compete” with SAA for CLA-1/SR-BI binding.[72] (For example, it has already been documented in the literature that both apoA-I and SAA are substrates for SR-BI, which indicates that SR-BI could mediate the transport of both proteins across the BBB (e.g.,[74])). Not surprisingly, therefore, Robert et al. have recently asserted that many lines of evidence suggest a protective role for HDL and its major apolipoprotein (apo)A-I in Alzheimer's disease.[14] Accordingly, a similar benefit (of “competitive binding” to SR-BI receptors) may well accompany the clinical intravenous use of the LCM/ND lipid nanoemulsion vehicle—which has already been repeatedly described in the peer-reviewed literature (based upon numerous in vivo animal studies) as a targeted, apoA-I-based, (SR-BI mediated) drug-delivery agent (see Section 2). Moreover, by incorporating drug molecules into the LCM/ND lipid nanoemulsion type, one is likely to obtain a multitasking “combination therapeutic” capable of targeting cell-surface SR-BI. This (intravenous) colloidal-nanocarrier therapeutic would make it possible for various cell types, all potentially implicated in Alzheimer's disease[1,2] and/or (late-onset) dementia, to be simultaneously sought out and better reached for localized drug treatment of brain tissue in vivo.[39,40]
6. Conclusions
Microvascular endothelial dysfunction precedes, often by decades, the cognitive decline associated with Alzheimer's disease. The cardiovascular risk factors for this disease trigger widespread inflammation and oxidative stress, both of which can lead to BBB disruption. Past studies (e.g.,[75]) have shown that low-grade inflammation and endothelial dysfunction contribute to reduced information processing speed and executive functioning in an older population. These interacting processes involve pathophysiological cascades which lead to neuronal (intracellular) Ca2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually dementia. By incorporating 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. Such biomedical application of colloidal drug-nanocarriers can potentially be extended to the treatment of complex medical disorders like dementia. Various past studies indicate that inflammation plays an important role in the process of Aβ deposition and, therefore, the inhibition of inflammatory cascades may attenuate amyloidogenic processes – such as Alzheimer's disease. Hence, an effective preventive and therapeutic strategy could be based upon nanotargeting drug(s), using lipid nanocarriers, toward a major SAA receptor responsible for numerous SAA-mediated cell signaling events leading to cognitive decline and eventually Alzheimer's disease or (late-onset) dementia. Lastly, it has been reconfirmed in the current literature that receptor-mediated endocytosis/transcytosis via lipoprotein receptors, particularly scavenger receptors including SR-BI, remains a major route for drug delivery across the BBB; namely, recently published work has demonstrated that nanocomplexes can be readily transported into brain capillary endothelial cells (bovine and porcine) via SR-BI receptor-mediated endocytosis ([4]; see also [76-78]).
Acknowledgements
This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.
Conflicts of Interest
The authors declare no conflict of interest.
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