Treating Dementia Early: Limiting Cellular Damage in Brain Tissue
Cavitation-Control Technology Inc., Farmington, CT 06032, USA
Academic Editor: Michael Fossel
Special Issue: Treatment of Dementia
Received: December 27, 2018 | Accepted: June 10, 2019 | Published: June 17, 2019
OBM Geriatrics 2019, Volume 3, Issue 2, doi:10.21926/obm.geriatr.1902057
Recommended citation: D'Arrigo JS. Treating Dementia Early: Limiting Cellular Damage in Brain Tissue. OBM Geriatrics 2019; 3(2): 057; doi:10.21926/obm.geriatr.1902057.
© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Cognitive impairment late in life is associated with two dominant diseases in humans, i.e., Alzheimer's disease and small vessel cerebrovascular disease, both causing brain atrophy years before clinical symptoms are detected. In fact, vascular brain lesions are very common in people over 70 years old, and recent reviews (e.g., [1,2] for background information) provide much evidence that a large proportion of dementia cases may be attributable to cerebrovascular disease (see also [3,4] and below). These vascular lesions include alterations in density and morphology of cerebral microvasculature, and a blood-brain barrier (BBB) breakdown with leakage of blood-borne molecules (see  for recent animal data, and a description of human data contained in citations 4-6 therein). Accordingly, vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease, and is a frequent co-morbidity in the Alzheimer's patient (e.g., [5,6]; cf. [7,8,9,10,11,12]; see also below). On a worldwide basis, 47 million people had dementia in 2016; of these dementia patients, 60%-80% have Alzheimer's disease (e.g., [8,9,13,14]: cf. below). It is no surprise, therefore, that multiple epidemiological studies have shown a marked overlap among risk factors for small vessel cerebrovascular disease and late-onset Alzheimer's disease. Furthermore, growing data from brain imaging studies and various animal models suggest that cerebrovascular dysfunction may well preceed cognitive impairment and the onset of neurodegenerative changes in Alzheimer's disease [2,4].
Also consistent with all the above considerations, clinicians have recently reported  (after a detailed review of studies examining current strategies for dementia prevention) that human studies to date suggest that multifactorial intervention, emphasizing particularly physical exercise and amelioration of vascular risk factors, may hold the most promise for the prevention of cognitive decline. As recently reviewed by Barnes and Corkery , aging and cardiovascular disease risk factors have long been associated with diminished vascular function, often having clinical implications which can include brain health. Nevertheless, these authors report that the age-associated increase in blood pressure and impairment in vascular function often may be lessened or even reversed through changes in lifestyle behaviors. Greater amounts of habitual exercise and higher cardiorespiratory fitness are correlated with measurable beneficial effects on cerebrovascular health and cognition [15,16].
2. Endothelial Dysfunction, and Targeted Treatment for Early Dementia
It has been reconfirmed in the current literature that receptor-mediated endocytosis/ transcytosis via lipoprotein receptors, particularly scavenger receptors (including class B type I, i.e., SR-BI), remains a major route for drug delivery across the blood-brain barrier (see below). Accordingly, endothelial-cell modulation and repair is feasible by pharmacological targeting [1,2,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] via SR-BI receptors (cf. ). Recently, Fung et al.  specifically reported that SR-BI mediates the uptake and transcytosis of high-density lipoprotein (HDL) across brain microvascular endothelial cells (i.e., across the BBB). 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 [2,33,38,39,40] (cf. [41,42,43,44,45,46,47]).
This targeted-drug-delivery approach, using the proposed LCM/ND lipid nanoemulsion for treating the more common (late-onset) dementias, receives added impetus from continual findings of cerebrovascular pathology [1,48,49,50,51,52,53,54,55,56,57,58] and an apparent endothelium-dysfunction [2,38,39,40,41,42,43,44,45,46,54,59,60,61,62,63,64,65] in both Alzheimer’s disease and its major risk factors [1,2,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77]. This (intravenous) combination therapeutic would make it possible for various cell types, all potentially implicated in Alzheimer’s disease (see [1,2] for reviews; cf. [76,77]), to be simultaneously sought out and better reached for localized drug treatment of brain tissue in vivo  (cf. ).
Note also that various published findings, reviewed earlier , supply further (indirect) evidence indicating that SR-BI may well provide an effective route for receptor-mediated (endocytic) drug delivery. For example, SR-BI is known to mediate the cellular uptake of cholesterol esters from HDL. When combined with various factors concerning the heterogeneity of HDL particles as well as the well-documented multiligand capability of SR-BI, then SR-BI emerges as the most plausible candidate (of all lipoprotein receptors) for major involvement in the enhanced endocytosis of LCM/ND lipid nanoemulsion(s) for targeted drug delivery. The parallel which exists is that the previously documented similarities in lipid composition between HDL and LCM/ND nanoemulsion(s) can partially simulate or mimic the above-mentioned heterogeneity (i.e., subpopulations or subspecies) of HDL particles .
In addition, the “lipid-coated microbubble/nanoparticle” population(s), within the LCM/ND lipid nanoemulsion, have neither been found to agglomerate nor coalesce into any “microbubble/particle” structure larger than 5 μm, either in vitro or in vivo, thus the risk of air embolus is negligible. Acute intravenous toxicity studies of this (isotonic) LCM/ND nanoemulsion agent in rabbits and dogs were conducted at an independent GLP contractor. The acute intravenous LD50 in both species was found to be greater than 4.8 mL/kg (i.e., well beyond all intended clinical dosages). Furthermore, no signs of gross toxicity or mortality were observed at the dosage of 4.8 mL/kg. It has also been found in other animal toxicology studies that at (intended clinical) intravenous LCM/ND lipid nanoemulsion doses of 0.14 mL/kg given three times per week for 6 weeks in rats and (much higher intravenous doses of) 0.48 mL/kg given three times per week for 3 months in rabbits, there were no untoward changes in serum chemistry, liver functions, hematology, or clotting profile or histological changes in adrenals, bladder, brain, heart, kidney, liver, lungs, marrow, pituitary, spleen, testes, thyroid, or ureters .
3. LCM/ND Nanoemulsion Type, Lipid Cubic Phases, and Biomimetic Nanocarriers
The self-assembling LCM/ND lipid nanoemulsion class comprises nonionic lipids exclusively (cf. [80,81]) throughout its coated microbubble's and/or related nanoparticle's (i.e., related lipid polymorphs') supramolecular structures(s). This biobased lipid composition of LCM/ND nanoemulsions (i.e., comprising glycerides and cholesterol compounds) is similar to lipids contained in several types of plama lipoproteins; accordingly, when these LCM/ND nanoemulsion particles are injected into the bloodstream, they likely acquire (i.e., bind) plasma apolipoprotein(s)–including notably apoA-I . While most early studies with LCM/ND nanoemulsions focused on its “lipid-coated microbubble (LCM) subpopulation” which rapidly targeted various tumors and neuroinjury sites, the same targeted drug-delivery attributes can logically be expected also from a colloidal (liquid-crystalline) “lipid nanoparticle subpopulation” in the LCM/ND nanoemulsion–since both categories of stable colloidal species (i.e., LCM and nanoparticles) are formed simultaneously in the stable nanoemulsion using the same (earlier-patented) mixture of powdered solid lipid surfactants. Basically, this patented mixture of lipid compounds comprises saturated glycerides (with acyl chain lengths greater than 10 carbons) combined with cholesterol and cholesterol esters. Moreover, later studies (using improved versions of various particle-sizing instruments) uncovered evidence that the vast majority of the LCM/ND nanoemulsion's lipid “microbubble/nano-particle” population exhibits diameters less than 1.0 μm .
Importantly, monoglyceride is the largest single-lipid fraction (by wt. %) of the powdered solid lipid surfactants used to produce the (Filmix®) LCM/ND nanoemulsions . As a group, monoglycerides exhibit different phase behaviors when they are exposed to water  (cf. [83,84,85,86]). In agreement with numerous other investigators, Kaasgaard and Drummond  also state that all these types of liquid-crystalline phases are frequently stable in excess water, which facilitates the preparation of nanoparticle dispersions and makes them suitable candidates for the encapsulation and controlled release of drugs (cf. [88,89,90,91,92,93,94]).
In particular, the self-assembly of varied and useful dispersed cubic phases (among other liquid-crystalline phases) depends heavily on the acyl chain length of the glycerides (primarily monoglycerides) placed in contact with water . There is great interest to utilize these dispersed cubic phases for the administration of drugs, or for the formulation of new delivery systems . The (lyotropic or solvent-induced) cubic liquid-crystalline phases may be classified into two distinct classes: Bicontinuous cubic phases [95,96,97,98,99] and micellar or discontinuous (e.g., type Fd3m) cubic phases . As reviewed by Garg et al. , monoglycerides spontaneously form bicontinuous cubic phases upon the addition of water, are relatively insoluble (allowing the formation of colloidal dispersions of cubic phases), and are resistant to changes in temperature. Accordingly, lipid nanoparticles comprising interior liquid-crystalline structures of curved lipid membranes (i.e., dispersed cubic phases) have been used to solubilize, encapsulate, and deliver medications to disease areas within the body  (see also [100,101,102,103,104,105,106,107,108,109,110,111]).
In addition to the above-described category of various bicontinuous cubic phases, the other above-named category referred to as “micellar or discontinuous” cubic phases is also worthy of comment at this point. Of particular interest within this latter category is the well-studied micellar cubic structure of the type Fd3m (which is often denoted by the number Q227) (e.g., [94,112]). Luzzati and coworkers have reported that this Fd3m cubic phase evidently requires a heterogeneous mixture of polar lipids [112,113]: Using the lipid examples they cite (and the lipid classification system of Small ), this Fd3m phase apparently must include both at least one (sufficiently polar) insoluble swelling amphiphilic lipid (e.g., monoglyceride [112,113]) and at least one (weakly polar) insoluble nonswelling amphiphilic lipid (e.g., diglyceride and/or cholesterol [112,113,114]; see also [115,116,117,118]) in order to self-assemble properly in (excess) water. Hence, 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 [80,81]) specifically include cholesterol and three categories of (saturated) glycerides, that is, tri-, di-, and monoglycerides (see [80,81]). In view of all the advantageous attributes of monoglycerides (recounted in the preceding paragraphs), 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 (see also  for a detailed review).
Besides certain glyceride-based liquid-crystalline systems displaying colloidal stability in excess water, the same important attribute has been documented for cholesterol and cholesterol esters – all of which are present in LCM/ND nanoemulsion formulations . For example, cholesterol and its esters change the packing structure of lipids, and in high concentrations they are known to induce the formation of a liquid-crystal phase . In addition, Kuntsche et al. [120,121] have prepared lipid nanoparticles in the (mesomorphic or) liquid-crystalline phase from cholesterol esters with saturated acyl chains. In accord with the above observations and considerations, the substantial concentrations of cholesterol esters and cholesterol in the LCM/ND nanoemulsion formulation likely further contribute to the known long-term stability of this nanoemulsion's (liquid-crystalline) lipid nanoparticles in excess water, thereby providing a persistent carrier matrix upon exposure to liquids such as blood plasma .
To conclude, self-assembled (colloidal mesophase) lipid nanoemulsions (e.g., [95,96,97,98,99,100]), particularly those predominantly containing dispersed cubic-phase lipid nanoparticles (e.g., [101,102,103,104,105]), continue to receive growing attention in pharmaceutical and/or biological fields. The main reason behind much of this attention is the fact that nonlamellar lipid nanostructures, such as cubic liquid-crystalline phases, have wide potential as delivery systems for numerous drugs, cosmetics, and food applications (e.g., [106,107,108]). A recurring example of a largely monoglyceride-based drug-delivery agent category is the multitasking LCM/ND nanoemulsion formulation (cf. above). In this particular targeted-delivery approach, the self-assembled “lipid particle” structure itself (upon intravenous injection of the LCM/ND nanoemulsion) is apparently successfully utilized as the “active” targeting ligand–which is directed via (adsorption of) plasma lipoproteins toward the appropriate receptors on the target-cell surface. These dispersed liquid-crystalline lipid particles, of the LCM/ND nanoemulsion formulation, are colloidally stable nanocarriers which very likely represent liquid-crystalline inverse-topology nanotransporters (nanocarriers), i.e., dispersed lipid cubic phases (cf. ).
4. Calcium Dyshomeostasis, and the Amyloid-β Ion Channel Hypothesis of Alzheimer's Disease
As explained in many reviews (e.g., [122,123,124]) by different investigators, it has been recognized for over two decades that disturbance of the intracellular calcium homeostasis is deeply involved in various aspects of the pathophysiology of several neurodegenerative disorders. As concerns Alzheimer's disease, it is believed by many researchers that enhanced calcium load may be brought about by extracellular accumulation of amyloid-β(Aβ) in the brain [122,123]. (In a subsequent review by Liao et al. , it is explained that this loss of calcium homeostasis is known to cause both the hyperphosphorylation of tau, resulting in neurofibillary tangles, and eventual neurodegeneration. Moreover, these authors further provide evidence supporting an updated amyloid cascade hypothesis, framing tau hyperphosphorylation as a cellular event between Aβ triggering and final synaptic deficits–which are strongly correlated with cognitive decline . Therefore, blocking of the initial (soluble-)Aβ triggering event can be seen as a crucial goal in treating dementia early (see below).) Such studies have laid the foundation for the popular idea that amyloid-β peptides (39-42 amino acid molecules) are, in part, toxic to brain tissue because they form aberrant ion channels in cellular membranes and thereby disrupt Ca2+ homeostasis in brain tissue and increase intracellular Ca2+. More specifically, later studies indicated that soluble forms of Aβ facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration [122,123].
The precise cellular pathway(s) by which the amyloid-β peptides bring about excitotoxic neurodegeneration has been much debated. A common cellular picture used to explain the disruptive effect of calcium dyshomeostasis within brain tissue, appearing often in the literature (e.g., [126,127]), involves a central role for the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in cognition and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This “Ca2+ dyshomeostasis”-induced excitotoxicity occurs when uncontrolled glutamate release surpasses the capacity of astrocytic clearance mechanisms, and is linked to several neurodegenerative disorders including Alzheimer's disease  (cf. ). (More generally, it should also be noted that various other alterations of intracellular signaling can lead to neurovascular degeneration. For example, Calabrese and coworkers  describe the major pathogenic factors involved in vascular cognitive impairment, emphasizing the relevance of cerebrocellular stress and neurohormetic responses to neurovascular insult. Similarly, this research group has recently  discussed various cellular mechanisms (e.g., oxidant/antioxidant status, oxidative stress, and the vitagene network) underlying Alzheimer's-disease neuroinflammatory pathogenesis that are contributory to Alzheimer's disease [56,128,129].)
Historical support for the above amyloid-β ion channel hypothesis, or so-called “calcium hypothesis”, has also been observed at the clinical level . Namely, there is little correlation between the amounts of fibrillar (insoluble) deposit at autopsy and the clinical severity of Alzheimer's disease. In contrast, a good correlation exists between early cognitive impairment and levels of soluble forms of Aβ in the brain . (Aggregation of Aβ proceeds from formation of soluble (low molecular weight) spherical oligomers toward eventually assuming a final and stable conformation as insoluble fibrils from which amyloid-β plaques are constituted. Neurotoxicity is associated with soluble aggregates (i.e., oligomers) of Aβ rather than with the plaques themselves . Moreover, recent studies [132,133] have found that the concentration of soluble Aβ oligomers (in aqueous brain lysates) from patients with early Alzheimer's-disease dementia was significantly higher than (in aqueous brain lysates) from patients with comparable Aβ-plaque burden but no dementia. These authors hypothesized that Aβ plaques could serve as binding reservoirs (sinks) or buffers for toxic soluble Aβ oligomers, sequestering them from other targets in the extracellular space and thereby preventing their toxicity. At early stages, the Aβ plaques could adequately buffer soluble oligomers, thereby protecting nearby neuropil from toxicity; whereas at later times if buffering capacity was lost or overwhelmed, soluble Aβ oligomers could be free to diffuse in the extracellular space and exert toxicity [132,133].) Accordingly, related experimental work has already shown that application of soluble Aβ oligomers (but not monomers or fibrils) to cultured neuroblastoma cells evoked large increases in cytosolic calcium that arise largely through Ca2+ influx across the plasma membrane .
As summarized by Di Scala et al. , the structure of amyloid pores has been extensively studied by ultrastructural methods. In particular, one group of investigators recently applied strategies (widely used to examine the structure of membrane proteins) to study the two major Aβ variants, namely, Aβ(1-40) and Aβ(1-42). Under the optimized detergent-micelle conditions employed: 1) Aβ(1-40) aggregated into amyloid fibrils; 2) contrariwise, Aβ(1-42) assembled into oligomers that inserted into lipid bilayers as well-defined pores . (These amyloid pores adopted characteristics of a β-barrel arrangement). Because Aβ(1-42), relative to Aβ(1-40), has a more prominent role in Alzheimer's disease, the higher propensity of Aβ(1-42) to form β-barrel pore-forming oligomers is an indication of their importance in Alzheimer's disease . Very recently, a different research group reported very similar findings . As background for their study, these latter authors point out that: elevated Aβ(1-42) plasma levels have been correlated with the progression of late-onset forms of Alzheimer's disease; Aβ(1-42) is significantly more neurotoxic than Aβ(1-40) both in vivo and in neuronal cell culture; and memory impairment is believed to be driven by Aβ(1-42) disruption of long-term (hippocampal) potentiation. In accordance with these considerations, these authors' own detailed experimental data  indicated that Aβ(1-42) assemblies in oligomeric preparations form ion channels (in membranes excised from cells of neuronal origin). In contrast, Aβ(1-40) oligomers, fibrils, and monomers did not form channels. Moreover, ion channel conductance results suggested that Aβ(1-42) oligomers, but not monomers and fibrils, formed pore structures. The authors concluded that their findings demonstrate that only Aβ(1-42) contains unique structural features that facilitate membrane insertion and channel formation, now aligning ion channel formation with the neurotoxic effect of Aβ(1-42) compared to Aβ(1-40) in Alzheimer's disease . (In addition, very recent in vivo experiments in rodents  have shown that cerebrospinal fluid enters the brain tissue along arterial perivascular spaces, and this flow plays a vital role in driving the clearance of toxic proteins such as Aβ(1-42)  from the interstitial fluid at more downstream locations. Detailed data analysis confirms that pumping of the heart, along with vascular wall kinetics (perivascular pumping), directly drive pulsatile cerebrospinal fluid bulk flow through the spaces between brain cells–thus clearing potentially toxic proteins into the bloodstream [136,137]. There is a decline in such clearance activity throughout the normal older adult lifespan, allowing buildup of Aβ(1-42) in brain tissue ; this buildup can accordingly be expected to facilitate membrane insertion of Aβ(1-42) and subsequent amyloid pore formation.
5. Renewed Promise of Bexarotene (or Analogs) to Inhibit Cognitive Decline in Humans
The preceding discussion of amyloid pore formation, in the cellular membranes of brain tissue, leads to another important consideration–the role of cholesterol. Namely, cholesterol is required for the assembly of amyloid pores formed by Aβ(1-42) . Therefore, an amphipathic drug (such as bexarotene) which competes with cholesterol for binding to Aβ(1-42) would be capable of preventing oligomeric channel formation (at least in vitro). Such a strategy has already been contemplated for the treatment of Alzheimer's and other neurodegenerative diseases that involve cholesterol-dependent toxic oligomers . However, when oral administration of bexarotene was employed subsequently in a Phase Ib (proof of mechanism) clinical trial , bexarotene displayed poor CNS penetration in normal human subjects. (Hence, the observed absence of an effect on Aβ metabolism was likely reflective of the low CNS-levels of bexarotene achieved  (cf. ).)
Nonetheless, at least two recently published reports (both in 2017) on bexarotene indicate a continuing interest in the ability of this FDA-approved (anticancer) drug to: 1) bind free Aβ peptide, as well as 2) bexarotene's previously reported positive effects in Alzheimer's-disease mouse models [141,142] (cf. [143,144,145]). Such past studies in animal models of Alzheimer's disease, concerning the beneficial effects of bexarotene, have also motivated a detailed analysis by Fantini et al.  to elucidate the mechanisms underlying the anti-Alzheimer properties of bexarotene in brain cells. These investigators demonstrated that bexarotene shares structural analogy with cholesterol: both bexarotene and cholesterol are amphipathic compounds, with a large apolar part consisting of a succession of hydrocarbon rings and a small polar headgroup (hydroxyl for cholesterol, carboxylate for bexarotene). Because it is the first drug that can both inhibit the binding of cholesterol to Aβ(1-42) and prevent calcium-permeable amyloid pore formation in the plasma membrane of brain cells, bexarotene might be considered as the prototype of a new class of anti-Alzheimer compounds . (Note that because bexarotene shares structural analogy with cholesterol, and the above-described LCM/ND nanoemulsion contains substantial concentrations of cholesterol esters and cholesterol (see above), incorporation of the bexarotene molecule into the LCM/ND nanocarrier is expected to represent an uncomplicated, straightforward formulation procedure commercially.) Moreover, Casali et al.  have very recently reported that treatment of an Alzheimer's-disease mouse model with (this FDA-approved anticancer drug) bexarotene resulted in enhanced cogniton in the APP/PS1 mice which resembled earlier findings. Strikingly, the authors observed sustained cognitive improvements in the mice even when bexarotene treatment was discontinued for 2 weeks. Also, they observed a sustained reduction in microgliosis and plaque burden, following drug withdrawal, exclusively in the hippocampus. Casali et al. concluded that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in Alzheimer's-disease (APP/PS1) mice .
Additional molecular aspects, concerning the membrane-related mechanisms for the known neuroprotective effect, of bexarotene action on brain tissue continue to be suggested and/or described in the recent literature (cf. [148,149]). In the most recently published study, Kamp et al.  show by NMR and CD spectroscopy that bexarotene directly interacts with the transmembrane domain of the amyloid precursor protein (APP) in a region where cholesterol binds. (Note that Aβ peptides are derived from APP, by the sequential action of β- and γ-secretases. γ-Secretase cleavage occurs in the transmembrane domain, of the C-terminal fragment left by β-secretase cleavage, and results in the release of Aβ peptides of various lengths . The longer, neurotoxic, Aβ(1-42) peptide is highly aggregation prone and represents the major Aβ species deposited in the brain [150,151,152,153]. Cholesterol promotes Aβ(1-42) aggregation by enhancing its primary nucleation rate by up to 20-fold .) Kamp et al. argue that their data  suggest that bexarotene is a pleiotropic molecule that interferes with Aβ metabolism through multiple mechanisms. More specifically, earlier work by Di Scala et al.  provided evidence that bexarotene competed with cholesterol for binding to Aβ and prevented oligomeric channel formation. Di Scala et al. argue that their findings indicate that it is possible to prevent the generation of neurotoxic oligomers by targeting the cholesterol-binding domain of Aβ peptides . Note that such blocking of amyloid-β-induced neurotoxic pore formation can be expected to avoid exacerbation of blood-brain barrier breakdown, already occurring at lower levels in aged humans with cognitive decline , and thereby prevent reaching higher levels of BBB breakdown associated with cognitive impairment (and/or eventually dementia) in late-onset Alzheimer's disease [154,155,156]. The known neuroprotective effect of beraxotene action on brain tissue has also recently stimulated expanded research into the use of a bexarotene derivative (i.e., an analog), which demonstrated the successful attenuation of Alzheimer's disease-related pathologies and cognitive impairments in an Alzheimer's-disease mouse model  (see also [158,159]).
Lastly, when considering the entire literature on oligomeropathics as well as the pathogenesis of Alzheimer's disease as a whole, Forloni et al.  point out in their review that the molecular mechanisms of oligomer-related toxic effects can be summarized under three different types of interactions (that are not necessarily mutually exclusive): amyloid-pore channel formation; direct or indirect action on specific cellular receptors; and nonspecific perturbance of cellular and intracellular membranes. Accordingly, very recently Mroczko et al.  have asserted that the causative role of Aβ(1-42) aggregation in the pathogenesis of Alzheimer's disease has been under debate for over 25 years. Strikingly, however, further analysis by Evangelisti et al.  has revealed the existence of a linear correlation between the level of the influx of Ca2+ across neuronal membranes, that triggers cellular damage, and the fraction of Aβ(1-42) oligomers bound to the membrane (; cf. [134,135]).
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 (SR-BI), and crosses the BBB. Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment. This in vivo targeting advantage may be particularly important for repurposing an FDA-approved drug (such as the anticancer drug bexarotene) which up to now, by itself (i.e., without nanocarrier), has previously displayed poor CNS penetration in human subjects.
This research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors.
Joseph S. D'Arrigo did all works.
Conflicts of Interest
The authors declare no conflict of interest. J.S.D. is employed at Cav-Con Inc.
- D'Arrigo JS. Alzheimer’s disease, brain injury, and CNS nanotherapy in humans: Sonoporation augmenting drug targeting. Med Sci. 2017; 5: 29. [CrossRef]
- D'Arrigo JS. Nanotherapy for Alzheimer’s disease and vascular dementia: Targeting senile endothelium. Adv Colloid Interface Sci. 2018; 251: 44-54. [CrossRef]
- Tariq S, d'Esterre CD, Sajobi TT, Smith EE, Longman RS, Frayne R, et al. A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non-demented patients with transient ischemic attack: The PREVENT study. BMC Geriatr. 2018; 18: 163. [CrossRef]
- Stefanova NA, Maksimova KY, Rudnitskaya EA, Muraleva NA, Kolosova NG. Association of cerebrovascular dysfunction with the development of Alzheimer's disease-like pathology in OXYS rats. BMC Genomics. 2018; 19: 75. [CrossRef]
- Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta Neuropathol. 2016; 131: 659-685. [CrossRef]
- Duncombe J, Kitamura A, Hase Y, Ihara M, Kalaria RN, Horsburgh K. Chronic cerebral hypoperfusion: A key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin Sci. 2017; 131: 2451-2468. [CrossRef]
- D'Arrigo JS. Targeting early dementia: Using lipid cubic phase nanocarriers to cross the blood-brain barrier. Biomimetics. 2018; 3: 4. [CrossRef]
- D'Arrigo JS. Treating early dementia: Drug targeting and circumventing the blood-brain barrier. Geriatr Med Care. 2018; 1: 1-7. [CrossRef]
- Dichgans M, Leys D. Vascular cognitive impairment. Circ Res. 2017; 120: 573-591. [CrossRef]
- Greenberg SM. Vascular disease and neurodegeneration: Advancing together. Lancet Neurol. 2017; 16: 333. [CrossRef]
- Perrotta M, Lembo G, Carnevale D. Hypertension and dementia: Epidemiological and experimental evidence revealing a detrimental relationship. Int J Mol Sci. 2016; 17: 347. [CrossRef]
- Sudduth TL, Weekman EM, Price BR, Gooch JL, Woolums A, Norris CM, et al. Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience. 2017; 341: 42-51. [CrossRef]
- Bhat NR. Vasculoprotection as a convergent, multi-targeted mechanism of anti-AD therapeutics and interventions. J Alzheimers Dis. 2015; 46: 581-591. [CrossRef]
- Alzheimer's Disease International. World Alzheimer Report 2016. Final report. London: Alzheimer's Disease International; February 20, 2016. Available from: www.alz.co.uk/worldreport2016
- Rakesh G, Szabo ST, Alexopoulos GS, Zannas AS. Strategies for dementia prevention: Latest evidence and implications. Ther Adv Chronic Dis. 2018; 8: 121-136. [CrossRef]
- Barnes JN, Corkery AT. Exercise improves vascular function, but does this translate to the brain? Brain Plasticity. 2018; 4: 65-79. [CrossRef]
- Srimanee A, Regberg J, Hallbrink M, Vajragupta O, Langel U. Role of scavenger receptors in peptide-based delivery of plasmid DNA across a blood–brain barrier model. Int J Pharm. 2016; 500: 128-135. [CrossRef]
- De Boer AG, van der Sandt ICJ, Gaillard PJ. The role of drug transporters at the blood–brain barrier. Annu Rev Pharmacol Toxicol. 2003; 43: 629-656. [CrossRef]
- Almer G, Mangge H, Zimmer A, Prassl R. Lipoprotein-related and apolipoprotein-mediated delivery systems for drug targeting and imaging. Curr Med Chem. 2015; 22: 3631-3651. [CrossRef]
- Preston JE, Abbott J, Begley DJ. Transcytosis of macromolecules at the blood–brain barrier. Adv Pharmacol. 2014; 71: 147-163. [CrossRef]
- Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF. Vascular dysfunction in the pathogenesis of Alzheimer’s disease—A review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol Dis. 2015; 82: 593-606. [CrossRef]
- Salmina AB, Inzhutova AI, Malinovskaya NA, Petrova MM. Endothelial dysfunction and repair in Alzheimer-type neurodegeneration: Neuronal and glial control. J Alzheimers Dis. 2010; 22: 17-36. [CrossRef]
- Tong XK, Hamel E. Simvastatin restored vascular reactivity, endothelial function and reduced string vessel pathology in a mouse model of cerebrovascular disease. J Cereb Blood Flow Metab. 2015; 35: 512-520. [CrossRef]
- Carradori D, Gaudin A, Brambilla D, Andrieux K. Application of nanomedicine to the CNS diseases. Int Rev Neurobiol. 2016; 130: 73-113. [CrossRef]
- Koster KP, Thomas R, Morris AW, Tai LM. Epidermal growth factor prevents oligomeric amyloid-induced angiogenesis deficits in vitro. J Cereb Blood Flow Metab. 2016; 36: 1865-1871. [CrossRef]
- Zenaro E, Piacentino G, Constantin G. The blood–brain barrier in Alzheimer’s disease. Neurobiol Dis. 2016; 107: 41-56. [CrossRef]
- Qosa H, Mohamed A, Al Rihani SB, Batarseha YS, Duong QV, Keller JN, et al. High-throughput screening for identification of blood–brain barrier integrity enhancers: A drug repurposing opportunity to rectify vascular amyloid toxicity. J Alzheimers Dis. 2016; 53: 1499-1516. [CrossRef]
- Hostenbach S, D’haeseleer M, Kooijman R, De Keyser J. The pathophysiological role of astrocytic endothelin-1. Prog Neurobiol. 2016, 144, 88-102. [CrossRef]
- Koizumi K, Wang G, Park L. Endothelial dysfunction and amyloid-induced neurovascular alterations. Cell Mol Neurobiol. 2016; 36: 155-165. [CrossRef]
- Goldwaser EL, Acharya NK, Sarkar A, Godsey G, Nagele RG. Breakdown of the cerebrovasculature and blood–brain barrier: a mechanistic link between diabetes mellitus and Alzheimer’s disease. J Alzheimers Dis. 2016; 54: 445-456. [CrossRef]
- Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging (Albany, NY). 2014; 6: 707-717. [CrossRef]
- Mahringer A, Reichel V, Ott M, MacLean C, Reimold I, Hollnack-Pusch E, et al. Overcoming the blood brain barrier: The challenge of brain drug targeting. J Nanoneurosci. 2012; 2: 5-19. [CrossRef]
- Robert J, Button EB, Stukas S, Boyce GK, Gibbs E, Cowan CM, et al. High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture. Mol Neurodegener. 2017; 12: 60. [CrossRef]
- Vishnyakova TG, Bocharov AV, Baranova IN, Chen Z, Remaley AT, Csako G, et al. Binding and internalization of lipopolysaccharide by CLA-1, a human orthologue of rodent scavenger receptor B1. J Biol Chem. 2003; 278: 22771-22780. [CrossRef]
- Darlington D, Li S, Hou H, Habib A, Tian J, Gao Y, et al. Human umbilical cord blood-derived monocytes improve cognitive deficits and reduce amyloid-pathology in PSAPP mice. Cell Transplant. 2015; 24: 2237-2250. [CrossRef]
- Chang EH, Rigotti A, Huerta P. Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition. Neurobiol Aging. 2009; 30: 407-419. [CrossRef]
- Fung KY, Wang C, Nyegaard S, Heit B, Fairn GD, Lee WL. SR-BI mediated transcytosis of HDL in brain microvascular endothelial cells is independent of caveolin, clathrin, and PDZK1. Front Physiol. 2017; 8: 841. [CrossRef]
- Robert J, Stukas S, Button E, Cheng WH, Lee M, Fan J, et al. Reconstituted high-density lipoproteins acutely reduce soluble brain A levels in symptomatic APP/PS1 mice. Biochim Biophys Acta. 2016; 1862: 1027-1036. [CrossRef]
- Armstrong SM, Sugiyama MG, Fung KYY, Gao Y, Wang C, Levy AS, et al. A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis. Cardiovasc Res. 2015; 108: 268-277. [CrossRef]
- Hottman DA, Chernick D, Cheng S, Wang Z, Li L. HDL and cognition in neurodegenerative disorders. Neurobiol Dis. 2014; 72: 22-36. [CrossRef]
- Velagapudi S, Yalcinkaya M, Piemontese A, Meier R, Norrelykke SF, Perisa D, et al. VEGF-A regulates cellular localization of SR-BI as well as transendothelial transport of HDL but not LDL. Arterioscler Thromb Vasc Biol. 2017; 37: 794-803. [CrossRef]
- Choi HJ, Seo EH, Yi D, Sohn BK, Choe YM, Byun MS, et al. Amyloid-independent amnestic mild cognitive impairment and serum apolipoprotein A1 levels. Am J Geriatr Psychiatr. 2016; 24: 144-153. [CrossRef]
- Kitamura Y, Usami R, Ichihara S, Kida H, Satoh M, Tomimoto H, et al. Plasma protein profiling for potential biomarkers in the early diagnosis of Alzheimer’s disease. Neurol Res. 2017; 39: 231-238. [CrossRef]
- Lazarus J, Mather KA, Armstrong NJ, Song F, Poljak A, Thalamuthu A, et el. DNA methylation in the apolipoprotein-A1 gene is associated with episodic memory performance on healthy older individuals. J Alzheimers Dis. 2015; 44: 175-182. [CrossRef]
- Ma C, Li J, Bao Z, Ruan Q, Yu Z. Serum levels of apoA1 and apoA2 are associated with cognitive status in older men. Biomed Res Int. 2015; 2015: 481621. [CrossRef]
- Slot RE, Van Harten AC, Kester MI, Jongbloed W, Bouwman FH, Teunissen CE, et al. Apolipoprotein A1 in cerebrospinal fluid and plasma and progression to Alzheimer’s disease in non-demented elderly. J Alzheimers Dis. 2017; 56: 687-697. [CrossRef]
- Yin ZG, Li L, Cui M, Zhou SM, Yu MM, Zhou HD. Inverse relationship between apolipoprotein A-I and cerebral white matter lesions: A cross-sectional study in middle-aged and elderly subjects. PLoS ONE. 2014; 9: e97113. [CrossRef]
- Weekman EM, Sudduth TL, Caverly CN, Kopper TJ, Phillips OW, Powell DK, et al. Reduced efficacy of anti-A immunotherapy in a mouse model of amyloid deposition and vascular cognitive impairment comorbidity. J Neurosci. 2016; 36: 9896-9907. [CrossRef]
- Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta. 2016; 1862: 887-900. [CrossRef]
- Kapasi A, Schneider JA. Vascular contributions to cognitive impairment, clinical Alzheimer’s disease, and dementia in older persons. Biochim Biophys Acta. 2016; 1862: 878-886. [CrossRef]
- McAleese KL, Alafuzoff I, Charidimou A, De Reuck J, Grinberg LT, Hainsworth AH, et el. Post-mortem assessment in vascular dementia: advances and aspirations. BMC Med. 2016; 14: 129. [CrossRef]
- Noh Y, Seo SW, Jeon S, Lee JM, Kim JS, Lee JH, et al. The role of cerebrovascular disease in amyloid deposition. J Alzheimers Dis. 2016; 54: 1015-1026. [CrossRef]
- Hishikawa N, Fukui Y, Sato K, Kono S, Yamashita T, Ohta T, et al. Cognitive and affective functions in Alzheimer’s disease patients with metabolic syndrome. Eur J Neurol. 2016; 23: 339-345. [CrossRef]
- Gutierrez J, Honig L, Elkind MS, Mohr JP, Goldman J, Dwork AJ, et al. Brain arterial aging and its relationship to Alzheimer dementia. Neurology. 2016; 86: 1507-1515. [CrossRef]
- Nagata K, Yamazaki T, Takano D, Maeda T, Fujimaki Y, Nakase T, et al. Cerebral circulation in aging. Ageing Res Rev. 2016; 30: 49-60. [CrossRef]
- Calabrese V, Giordano J, Signorile A, Ontario ML, Castorina S, de Pasquale C, et al. Major pathogenic mechanisms in vascular dementia: roles of cellular stress response and hormesis in neuroprotection. J Neurosci Res. 2016; 94: 1588-1603. [CrossRef]
- Toth P, Tarantini S, Csiszar A, Ungvari ZI. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol. 2017; 312: H1-H20. [CrossRef]
- Devraj K, Poznanovic S, Spahn C, Schwall G, Harter PN, Mittelbronn M, et al. BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease. J Cereb Blood Flow Metab. 2016; 36: 1281-1294. [CrossRef]
- Chao AC, Lee TC, Juo SH, Yang DI. Hyperglycemia increases the production of amyloid-peptide leading to decreased endothelial tight junction. CNS Neurosci Ther. 2016; 22: 291-297. [CrossRef]
- Khalil RB, Khoury E, Koussa S. Linking multiple pathogenic pathways in Alzheimer’s disease. World J Psychiatr. 2016; 6: 208-214. [CrossRef]
- Festoff BW, Sajja RK, van Dreden P, Cucullo L. HGMB1 and thrombin mediate the blood–brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease. J Neuroinflamm. 2016; 13: 194. [CrossRef]
- Gangoda SV, Butlin M, Gupta V, Chung R, Avolio A. Pulsatile stretch alters expression and processing of amyloid precursor protein in human cerebral endothelial cells. J Hypertens. 2016; 34: e24. [CrossRef]
- Roberts AM, Jagadapillai R, Vaishnav RA, Friedland RP, Drinovac R, Lin X, et al. Increased pulmonary arteriolar tone associated with lung oxidative stress and nitric oxide in a mouse model of Alzheimer’s disease. Physiol Rep. 2016; 4: e12953. [CrossRef]
- Shang S, Yang YM, Zhang H, Tian L, Jiang JS, Dong YB, et al. Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer’s disease mice. J Cereb Blood Flow Metab. 2016; 36: 1987-1991. [CrossRef]
- Austin SA, Katusic ZS. Loss of endothelial nitric oxide synthase promotes p25 generation and tau phosphorylation in a murine model of Alzheimer’s disease. Circ Res. 2016; 119: 1128-1134. [CrossRef]
- Katusic ZS, Austin SA. Neurovascular protective function of endothelial nitric oxide. Circ J. 2016; 1499-1503. [CrossRef]
- Wang L, Du Y, Wang K, Xu G, Luo S, He G. Chronic cerebral hypoperfusion induces memory deficits and facilitates A generation in C57BL/6J mice. Exp Neurol. 2016; 283: 353-364. [CrossRef]
- Kyrtsos CR, Baras JS. Modeling the role of the glymphatic pathway and cerebral blood vessel properties in Alzheimer’s disease pathogenesis. PLoS ONE. 2015; 10: e0139574. [CrossRef]
- Kalaria RN, Akinyemi R, Ihara M. Stroke injury, cognitive impairment and vascular dementia. Biochim Biophys Acta. 2016; 1862: 915-925. [CrossRef]
- Khan A, Kalaria RN, Corbett A, Ballard C. Update on vascular dementia. J Geriatr Psychiatry Neurol. 2016; 29: 281-301. [CrossRef]
- Austin SA, Santhanam AV, d’Uscio LV, Katusic ZS. Regional heterogeneity of cerebral microvessels and brain susceptibility to oxidative stress. PLoS ONE. 2015; 10: e0144062. [CrossRef]
- Toda N, Okamura T. Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: implications for Alzheimer’s disease. J Pharmacol Sci. 2016; 131: 223-232. [CrossRef]
- Uiterwijk R, Huijts M, Staals J, Rouhl RP, De Leeuw PW, Kroon AA, et al. Endothelial activation is associated with cognitive performance in patients with hypertension. Am J Hypertens. 2016; 29: 464-469. [CrossRef]
- Kamat PK, Kyles P, Kalani A, Tyagi N. Hydrogen sulfide ameliorates homocysteine-induced Alzheimer’s disease-like pathology, blood-brain barrier disruption, and synaptic disorder. Mol Neurobiol. 2016; 53: 2451-2467. [CrossRef]
- Iadecola C. Untangling neurons with endothelial nitric oxide. Circ Res. 2016; 119: 1052-1054. [CrossRef]
- Wang YJ. Lessons from immunotherapy for Alzheimer’s disease. Nat Rev Neurol. 2014; 10: 188-189. [CrossRef]
- Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer’s disease. Nat Rev Neurol. 2013; 9: 25-34. [CrossRef]
- D'Arrigo JS. Stable Nanoemulsions: Self-assembly in nature and nanomedicine. Amsterdam: Elsevier; 2011. 415 pp, ISBN 978-0-444-53798-0.
- Barbarese E, Ho SY, D’Arrigo JS, Simon RH. Internalization of microbubbles by tumor cells in vivo and in vitro. J Neurooncol. 1995; 26: 25-34. [CrossRef]
- D'Arrigo JS. Surfactant mixtures, stable gas-in-liquid emulsions, and methods for the production of such emulsions from said mixtures. U.S. Patent No. 4, 684, 479; issued 1987.
- D'Arrigo JS. Method for the production of medical-grade lipid-coated microbubbles, paramagnetic labeling of such microbubbles and therapeutic uses of microbubbles. U.S. Patent No. 5, 215, 680; issued 1993.
- Garg G, Saraf SH, Saraf SW. Cubosomes: An overview. Biol Pharm Bull. 2007; 30: 350-353. [CrossRef]
- Tanford C. The hydrophobic effect: Formation of micelles and biological membranes. New York: Wiley; 1973.
- Boyd BJ, Whittaker DV, Khoo SM, Davey G. Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems. Int J Pharm. 2006; 309: 218-226. [CrossRef]
- Pouton CW. Properties and uses of common formulation lipids, surfactants and cosurfactants. Proceedings of the AAPS Workshop--effective utilization of lipid-based systems to enhance the delivery of poorly soluble drugs: Physicochemical, biopharmaceutical and product development considerations; 5–6 March 2007; Bethesda, MD, USA. Arlington, VA: AAPS; 2007; Constantinides PP, Porter CJH, Eds.
- Small DM. The behavior of biological lipids. Pure Appl Chem. 1981; 53: 2095-2103. [CrossRef]
- Kaasgaard T, Drummond CJ. Ordered 2-D and 3-D nano-structured amphiphile self-assembly materials stable in excess solvent. Phys Chem Chem Phys. 2006; 8: 4957-4975. [CrossRef]
- Shearman GC, Khoo BJ, Motherwell ML, Brakke KA, Ces O, Conn CE, et al. Calculations of and evidence for chain packing stress in inverse lyotropic bicontinuous cubic phases. Langmuir. 2007; 23: 7276-7285. [CrossRef]
- Rizwan SB, Dong YD, Boyd BJ, Rades T, Hook S. Characterization of bicontinuous cubic liquid crystalline systems of phytantriol and water using cryo field emission scanning electron microscopy (cryo FESEM). Micron. 2007; 38: 478-485. [CrossRef]
- Yaghmur A, de Campo L, Sagalowicz L, Leser ME, Glatter O. Emulsified microemulsions and oil-containing liquid crystalline phases. Langmuir. 2005; 21: 569-577. [CrossRef]
- Yaghmur A, de Campo L, Sagalowicz L, Leser ME, Glatter O. Control of the internal structure of MLO-based isasomes by the addition of diglycerol monooleate and soybean phosphatidylcholine. Langmuir. 2006; 22: 9919-9927. [CrossRef]
- Gustafsson J, Ljusberg-Wahren H, Almgren M, Larsson K. Submicron particles of reversed lipid phases in water stabilized by a nonionic amphiphilic polymer. Langmuir. 1997; 13: 6964-6971. [CrossRef]
- De Campo L, Yaghmur A, Sagalowicz L, Leser ME, Watzke H, Glatter O. Reversible phase transitions in emulsified nanostructured lipid systems. Langmuir. 2004; 20: 5254-5261. [CrossRef]
- Yaghmur A, de Campo L, Salentinig S, Sagalowicz L, Leser ME, Glatter O. Oil-loaded monolinolein-based particles with confined inverse discontinuous cubic structure (Fd3m). Langmuir. 2006; 22: 517-521. [CrossRef]
- Abraham T, Hato M, Hirai M. Glycolipid based cubic nanoparticles: Preparation and structural aspects. Colloids Surf B Biointerfaces. 2004; 35: 107-117. [CrossRef]
- Larsson K. Aqueous dispersions of cubic lipid-water phases. Curr Opin Colloid Interface Sci. 2000; 5: 64-69. [CrossRef]
- Larsson K. Cubic lipid-water phases: Structures and biomembrane aspects. J Phys Chem. 1989; 93: 7304-7314. [CrossRef]
- Mezzenga R, Lee WB, Fredrickson GH. Design of liquid-crystalline foods in field theoretic computer simulations. Trends Food Sci Technol. 2006; 17: 220-226. [CrossRef]
- Schwarz US, Gompper G. Bending frustration of lipid-water mesophases based on cubic minimal surfaces. Langmuir. 2001; 17: 2084-2096. [CrossRef]
- Fong C, Wells D, Krodkiewska I, Booth J, Hartley PG. Synthesis and mesophases of glycerate surfactants. J Phys Chem B. 2007; 11: 1384-1392. [CrossRef]
- Worle G, Siekmann B, Koch MHJ, Bunjes H. Transformation of vesicular into cubic nanoparticles by autoclaving of aqueous monoolein/poloxamer dispersions. Eur J Pharm Sci. 2006; 27: 44-53. [CrossRef]
- Siekmann B, Bunjes H, Koch MHJ, Westesen K. Preparation and structural investigations of colloidal dispersions prepared from cubic-monoglyceride-water phases. Int J Pharm. 2002; 44: 33-43. [CrossRef]
- Rosenblatt KM, Douroumis D, Bunjes H. Drug release from differently structured monoolein/poloxamer nanodispersions studied with differential pulse polarography and ultrafiltration at low pressure. J Pharm Sci. 2007; 96: 1564-1575. [CrossRef]
- Worle G, Siekmann B, Bunjes H. Effect of drug loading on the transformation of vesicular into cubic nanoparticles during heat treatment of aqueous monoolein/poloxamer dispersions. Eur J Pharm Biopharm. 2006; 63:128-133. [CrossRef]
- Sagalowicz L, Leser ME, Watzke HJ, Michel M. Monoglyceride self-assembly structures as delivery vehicles. Trends Food Sci Technol. 2006; 17:204-214. [CrossRef]
- Benkendorf S, Hobbs HK, Wu SHW. Liquid-crystalline phase drug delivery vehicle. U.S. Patent No. 6,235,312; issued 2001.
- Heertje I, Kleinherenbrink FA, Sikking R, Van Der Meijs WC. Preparation of heat-treated mesomorphic phases in food products. U.S. Patent No. 5,939,128; issued 1999.
- Mezzenga R, Meyer C, Servais C, Romoscanu AI, Sagalowicz L, Hayward RC. Shear rheology of lyotropic crystals: a case study. Langmuir. 2005; 21: 3322-3333. [CrossRef]
- Mezzenga R, Grigorov M, Zhang Z, Servais C, Sagalowicz L, Romoscanu AI, et al. Polysaccharide-induced order-to-order transitions in lyotropic liquid crystals. Langmuir. 2005; 21: 6165-6169. [CrossRef]
- Shah MH, Biradar SV, Paradkar AR. Spray dried glyceryl monooleate-magnesium trisilicate dry powder as cubic phase precursor. Int J Pharm. 2006; 323: 18-26. [CrossRef]
- Fong C, Wells D, Krodkiewska I, Weerawardeena A, Booth J, Hartley PG, et al. Diversifying the solid state and lyotropic phase behavior of nonionic urea-based surfactants. J Phys Chem B. 2007; 111: 10713-10722. [CrossRef]
- Luzzati V, Vargas R, Mariani P, Gulik A, Delacroix H. Cubic phases of lipid-containing systems: elements of a theory and biological connotations. J Mol Biol. 1993; 229: 540-551. [CrossRef]
- Luzzati V, Vargas R, Gulik A, Mariani P, Seddon JM, Rivas E. Lipid polymorphism: a correction. The structure of the cubic phase of extinction symbol Fd–consists of two types of disjointed reverse micelles embedded in a three-dimensional hydrocarbon matrix. Biochemistry. 1992; 31: 279-285. [CrossRef]
- Nieva JL, Alonso A, Basanez G, Goni FM, Gulik A, Vargas R, et al. Topological properties of two cubic phases of a phospholipid:cholesterol: Diacylglycerol aqueous system and their possible implications in thephospholipid C-induced liposome fusion. FEBS Lett. 1995; 368: 143-147. [CrossRef]
- Seddon JM, Zeb N, Templer RH, McElhaney RN, Mannock DA. An Fd3m lyotropic cubic phase in a binary glycolipid/water system. Langmuir. 1996; 12: 5250-5253. [CrossRef]
- Delacroix H, Gulik-Krzywicki T, Seddon JM. Freeze fracture electron microscopy of lyotropic lipid systems: quanitative analysis of the inverse micellar cubic phase of space group Fd3m (Q227). J Mol Biol. 1996; 258: 88-103. [CrossRef]
- Seddon JM. An inverse face-centered cubic phase formed by diacylglycerol-phosphatidylcholine mixtures. Biochemistry. 1990; 29: 7997-8002. [CrossRef]
- Takahashi H, Hatta I, Quinn PJ. Cubic phases in hydrated 1:1 and 1:2 dipalmitoylphosphatidylcholine-dipalmitoylglycerol mixtures. Biophys J. 1996; 70: 1407-1411. [CrossRef]
- Amselem S, Friedman D. Solid fat nanoemulsions. U.S. Patent No. 5,662,932; issued 1997.
- Kuntsche J, Koch MJ, Drechsler M, Bunjes H. Crystallization behavior of supercooled smectic cholesteryl myristate nanoparticles containing phospholipids as stabilizers. Colloids Surf B Biointerfaces. 2005; 44: 25-35. [CrossRef]
- Kuntsche J, Westesen K, Drechsler M, Koch MHJ, Bunjes H. Supercooled smectic nanoparticles: A potential novel carrier system for poorly water soluble drugs. Pharm Res. 2004; 21: 1834-1843. [CrossRef]
- Nimmrich V, Eckert A. Calcium channel blockers and dementia. Brit J Pharmacol. 2013; 169: 1203-1210. [CrossRef]
- Shirwany NA, Payette D, Xie J, Guo Q. The amyloid beta ion channel hypothesis of Alzheimer's disease. Neuropsychiatr Dis Treat. 2007; 3: 597-612.
- Alzheimer's Association Calcium Hypothesis Workgroup. Calcium hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement. 2017; 13: 178-182. [CrossRef]
- Liao D, Miller EC, Teravskis PJ. Tau acts as a mediator for Alzheimer's disease-related synaptic deficits. Eur J Neurosci. 2014; 39: 1202-1213. [CrossRef]
- Rudy CC, Hunsberger HC, Weitzner DS, Reed MN. The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease. Aging Dis. 2015; 6: 131-148. [CrossRef]
- Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer's disease. Neurol Sci. 2016; 37: 1039-1047. [CrossRef]
- Salinaro AT, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, et al. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer's disease and Alzheimer-linked pathologies: Modulation by nutritional mushrooms. Immun Ageing. 2018; 15: 8. [CrossRef]
- Pennisi M, Crupi R, Di Paola R, Ontario ML, Bella R, Calabrese EJ, et al. Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease. J Neurosci Res. 2017; 95: 1360-1372. [CrossRef]
- Di Scala C, Yahi N, Boutemeur S, Flores A, Rodriguez L, Chahinian H, et al. Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein. Sci Rep. 2016; 6: 28781. [CrossRef]
- Demuro A, Smith M, Parker I. Single-channel Ca2+ imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology. J Cell Biol. 2011; 195: 515-524. [CrossRef]
- Brody DL, Jiang H, Wildburger N, Esparza TJ. Non-canonical soluble amyloid-beta aggregates and plaque buffering: Controversies and future directions for target discovery in Alzheimer's disease. Alzheimers Res Ther. 2017; 9: 62. [CrossRef]
- Esparza TJ, Gangolli M, Cairns NJ, Brody DL. Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls. PLoS ONE. 2018; 13: e0200251. [CrossRef]
- Serra-Batiste M, Ninot-Pedrosa M, Bayoumi M, Gairi M, Maglia G, Carulla N. Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proc Natl Acad Sci USA. 2016; 113: 10866-10871. [CrossRef]
- Bode DC, Baker MD, Viles JH. Ion channel formation by amyloid-β42 oligomers but not amyloid-β40 in cellular membranes. J Biol Chem. 2017; 292: 1404-1413. [CrossRef]
- Mestre H, Tithof J, Du T, Song W, Peng W, Sweeney AM, et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018; 9: 4878. [CrossRef]
- De Leon M, Pirraglia E, Osorio RS, Glodzik L, Saint-Louis L, Kim HJ, et al. The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease. PLoS ONE. 2018; 13: e0191240. [CrossRef]
- Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J. Interaction of Alzheimer's β-amyloid peptides with cholesterol: Mechanistic insights into amyloid pore formation. Biochemistry. 2014; 53: 4489-4502. [CrossRef]
- Ghosal K, Haag M, Verghese PB, West T, Veenstra T, Braunstein JB, et al. A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects. Alzheimers Dement. 2016; 2: 110-120. [CrossRef]
- Pierrot N, Lhommel R, Quenon L, Hanseeuw B, Dricot L, Sindic C, et al. Targretin [bexarotene] improves cognitive and biological markers in a patient with Alzheimer's disease. J Alzheimers Dis. 2016; 49: 271-276. [CrossRef]
- Mirza Z, Beg MA. Possible molecular interactions of bexarotene – a retinoid drug and Alzheimer's Aβ peptide: A docking study. Curr Alzheimer Res. 2017; 14: 327-334.
- Huy PDQ, Thai NQ, Bednarikova Z, Phuc LH, Linh HQ, Gazova Z, et al. Bexarotene does not clear amyloid beta plaques but delays fibril growth: Molecular mechanisms. ACS Chem Neurosci. 2017; 8: 1960-1969. [CrossRef]
- Mariani MM, Malm T, Lamb R, Jay TR, Neilson L, Casali B, et al. Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease. Sci Rep. 2017; 7: 42270. [CrossRef]
- Habchi J, Arosio P, Perni M, Costa AR, Yagi-Utsumi M, Joshi P, et al. An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease. Sci Adv. 2016; 2: e1501244. [CrossRef]
- Tousi B. The emerging role of bexarotene in the treatment of Alzheimer's disease: Current evidence. Neuropsychiatr Dis Treat. 2015; 11: 311-315. [CrossRef]
- Fantini J, Di Scala C, Yahi N, Troadec JD, Sadelli K, Chahinian H, et al. Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer's β-amyloid peptides. ACS Chem Neurosci. 2014; 5: 216-224. [CrossRef]
- Casali BT, Reed-Geaghan EG, Landreth GE. Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer's disease. J Neuroinflamm. 2018; 15: 43. [CrossRef]
- Tu L, Yang XL, Zhang Q, Wang Q, Tian T, Liu D, et al. Bexarotene attenuates early brain injury via inhibiting microglia activation through PPARγ after experimental subarachnoid hemorrhage. Neurol Res. 2018; doi:10.1080/01616412.2018.1463900 . [CrossRef]
- Dheer Y, Chitranshi N, Gupta V, Abbasi M, Mirzaei M, You Y, et al. Bexarotene modulates retinoid-X-receptor expression and is protective against neurotoxic endoplasmic reticulum stress response and apoptotic pathway activation. Mol Neurobiol. 2018; doi:10.1007/s12035-018-1041-9 [CrossRef]
- Kamp F, Scheidt HA, Winkler E, Basset G, Heinel H, Hutchison JM, et al. Bexarotene binds to the amyloid precursor protein transmembrane domain, alters its α-helical conformation, and inhibits γ-secretase nonselectivity in liposomes. ACS Chem Neurosci. 2018; doi: 10.1021acschemneuro.8b00068 .
- Serra-Batiste M, Tolchard J, Giusti F, Zoonens M, Carulla N. Stabilization of a membrane-associated amyloid-β oligomer for its validation in Alzheimer's disease. Front Mol Biosci. 2018; 5: 38. [CrossRef]
- Xiang N, Lyu Y, Zhu X, Narsimhan G. Investigation of the interaction of amyloid-β peptide (11-42) oligomers with a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane using molecular dynamics simulation. Phys Chem Chem Phys. 2018; 20: 6817-6829. [CrossRef]
- Habchi J, Chia S, Galvagnion C, Michaels TCT, Bellaiche MMJ, Ruggeri FS, et al. Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nat Chem. 2018; 10: 673-683. [CrossRef]
- Bowman GL, Dayon L, Kirkland R, Wojcik J, Peyratout G, Severin IC, et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. AD. 2018; doi: 10.1016/j.jalz.2018.06.2857 . [CrossRef]
- Wang H, Golob EJ, Su MY. Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls. J Magn Reson Imaging. 2006; 24: 695-700. [CrossRef]
- Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015; 85: 296-302. [CrossRef]
- Yuan C, Guo X, Zhou Q, Du F, Jiang W, Zhou X, et al. OAB-14, a bexarotene derivative, improves Alzheimer's disease-related pathologies and cognitive impairments by increasing β-amyloid clearance in APP/PS1 mice. Biochim Biophys Acta-Mol Basis Dis. 2019; 1865: 161-180. [CrossRef]
- Chia S, Habchi J, Michaels TCT, Cohen SIA, Linse S, Dobson CM, et al. SAR by kinetics for drug discovery in protein misfolding diseases. Proc Natl Acad Sci USA. 2018; 115: 10245-10250. [CrossRef]
- Habchi J, Chia S, Limbocker R, Mannini B, Ahn M, Perni M, et al. Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer's disease. Proc Natl Acad Sci USA. 2017; 114: E200-E208. [CrossRef]
- Forloni G, Artuso V, La Vitola P, Balducci C. Oligomeropathies and pathogenesis of Alzheimer's and Parkinson's diseases. Mov Disor. 2016; 31: 771-781. [CrossRef]
- Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P. Amyloid-β oligomers (AβOs) in Alzheimer's disease. J Neural Transm. 2018; 125: 177-191. [CrossRef]
- Evangelisti E, Cascella R, Becatti M, Marrazza G, Dobson CM, Chiti F, et al. Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases. Sci Rep. 2016; 6: 32721. [CrossRef]