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Open Access Review

Biomaterial to Improve Drug Delivery in Alzheimer's Disease: Linking Major Pathogenic Pathways

Joseph S. D'Arrigo 1, ‡, *

  1. Cavitation-Control Technology Inc., Farmington, CT 06032, USA

‡ Current Affiliation: Cav-Con Inc., Bellevue, WA 98007, USA

Correspondence: Joseph S. D'Arrigo

Academic Editor: Md. Golam Sharoar

Special Issue: Aging and Alzheimer’s Disease

Received: December 26, 2019 | Accepted: February 23, 2020 | Published: February 28, 2020

OBM Geriatrics 2020, Volume 4, Issue 1, doi:10.21926/obm.geriatr.2001110

Recommended citation: D'Arrigo JS. Biomaterial to Improve Drug Delivery in Alzheimer's Disease: Linking Major Pathogenic Pathways. OBM Geriatrics 2020; 4(1): 110; doi:10.21926/obm.geriatr.2001110.

© 2020 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.


Aging, hypertension, diabetes, obesity, atherosclerosis, traumatic brain injury, and other factors can all synergistically promote diverse pathological mechanisms. These risk factors trigger widespread inflammation and oxidative stress, both of which can lead to blood-brain barrier (BBB) disruption. These pathological cascades lead to neuronal Ca2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually Alzheimer's disease. 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. In addition, it has already been determined from past studies that drug-carrying lipid nanoparticles can take advantage of physiological receptor-mediated transport processes across the BBB for localized drug delivery in brain tissue.


Cognitive impairment; blood-brain barrier; Alzheimer's disease; drug targeting; nanoemulsion; neuroinflammation; proinflammatory cytokines; serum amyloid A

1. Background

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 (see [1,2] for reviews). By incorporating appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, and crosses the blood-brain barrier (BBB). Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment [3,4,5,6]. This (colloidal-nanocarrier) in vivo targeting advantage may be particularly important when delivering pleiotropic natural substances (e.g., an isoflavone) or for repurposing FDA-approved food additive(s) and/or drug(s), especially one which has shown the added ability to restore some cognitive functions in certain animal models of Alzheimer's disease [4].

2. Endothelial Dysfunction, and Targeted Treatment for Early Dementia

It has been reported repeatedly that endothelial modulation and repair is feasible by pharmacological targeting [1,2,7,8,9,10,11,12,13] of the SR-BI receptors (i.e., “scavenger receptor class B, type I”) [13,14]. Recently, Fung et al. 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) [15]. 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 [16,17,18].

This targeted (LCM/ND-delivery) type approach receives added impetus from continual findings of cerebrovascular pathology [1,19,20,21,22,23,24,25,26,27,28,29] and an apparent endothelium dysfunction [2,17,18,25,30,31,32,33,34,35,36] in both Alzheimer's disease and its major risk factors [1,2,29,30,31,32,33,34,35,36,37,38,39,40,41]. By incorporating drug molecules into the LCM/ND lipid nanoemulsion type (yielding particle sizes mostly < 0.1 μm in diameter – see Figure 1), known to be a successful drug carrier [42,43], one is likely to obtain a multitasking combination therapeutic capable of targeting cell-surface SR-BI.

Click to view original image

Figure 1 LCM/ND nanoemulsion stability over time. (Adapted from ref. [2]).

3. LCM/ND Nanoemulsion Type, and Targeting via Lipid Cubic Phases

Monoglycerides exhibit different phase behaviors when they are exposed to water [44,45,46,47,48,49,50]. 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 [51,52]) specifically include cholesterol and three categories of (saturated) glycerides, that is, tri-, di-, and monoglycerides [51,52]. 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 [42].

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 receptors on the target-cell surface [42].

4. Molecular Mechanism of Colloidal Nanocarrier Formation

Previous reports concerning colloidal nanocarriers [e.g., 5] do not fully explain how various (biobased) lipids, and their mixtures, are able to reliably form self-assembled non-lamellar nanostructures (i.e., lipid cubic phases) – which, in turn, have been observed to serve as colloidally stable nanocarriers for drug(s) in excess water (e.g., in blood plasma) [53]. The answer to this fundamental question resides in the physicochemical tendency of these biobased lipids to adopt a non-lamellar inverse topology. This special tendency, of these surface-active lipids, is itself a function of lipid head-group hydration, acyl chain length, and cholesterol content (see below).

As reviewed by Schwarz and Gompper [54], the predominance of the lamellar phase at ambient temperatures stems from the fact that (in contrast to many synthetic surfactants, which usually have large head groups and form micelles) lipids themselves have rather bulky hydrocarbon chains (e.g., [54,55,56]). Spontaneous curvature can be increased by changing molecular architecture, that is, by adding lipids with bulkier chains, or by replacing charged lipids with similar ones having only nonionic head groups to avoid Coulombic repulsion between head groups. Lipids with spontaneous curvature are often called “nonbilayer lipids”. Hence, with the resulting large spontaneous (negative or inverse) curvature, a cubic phase of inverse spherical micelles is often observed [54].

Notice that there is actual consensus that amphiphilic lipids with weakly hydrated, hydrophilic head groups serve to promote formation of an Fd3m cubic phase (also known as phase Q227) ([56]; cf. [57]), -- which is particularly relevant to the earlier-described [3] LCM/ND nanoemulsion formulation(s): Specifically, the saturated glycerides and cholesterol (and its ester derivatives), which together compose the basic Filmix® (LCM/ND) nanoemulsion formulation [42], are all nonionic and therefore each amphiphilic lipid in such a lipid mixture would only have a weakly hydrated, hydrophilic head group. Consequently, the above facts considered together support the earlier provisional conclusion that the dispersed Fd3m micellar cubic phase represents the most probable or preferred lipid polymorphic form adopted by the particles in the LCM/ND nanoemulsions [3,42].

As concerns the acyl chain length of the saturated glycerides contained in the LCM/ND nanoemulsion formulations, in relation to promoting formation of an Fd3m cubic phase (or Q227), it is useful to also consider related experimental work employing biological amphiphilic lipids having saturated acyl chain lengths (which include) from 12 carbon atoms to 16 carbon atoms long [see below]. Our focus on this specific range of chain lengths stems from the fact that the saturated (nonionic) glycerides in the “particularly preferred” lipid mixture, used to form LCM/ND nanoemulsions, have acyl chain lengths of 12 carbons (e.g., glycerol monolaurate) and 16 carbons (e.g., glycerol tripalmitate) in length [42,51,52]. Hence, it is relevant to note a study by Seddon et al. [58] concerning the phase behaviors of a homologous series of saturated phosphoglyceride/fatty acid mixtures having chain lengths of C12 and higher, which were analyzed by X-ray diffraction and colorimetry, as a function of water content. These investigators reported that the lamellar phase is suppressed in these lipid mixtures, being replaced by inverse non-lamellar phases for all (saturated acyl) chain lengths greater than C12, and at all levels of hydration ([58]; cf. [59]).

It was also stated earlier (in this section regarding adoption of non-lamellar topology) that cholesterol is another important component in the basic LCM/ND nanoemulsion formulation. This fact is consistent with published data from related experimental studies using phosphoglyceride bilayers: As summarized by Chen and Rand [60], cholesterol has been found to destabilize bilayers of some common biological phosphoglycerides, and to induce the formation of the inverse phase in these systems [61,62,63,64,65]. Specifically, while sterols cannot alone form lamellar structures, sterols like cholesterol appear to have evolved to fill the flickering spaces among the acyl chains in membrane bilayers (e.g., [66]). Furthermore, cholesterol has the unique capability among membrane lipids of rapidly “flip-flopping” (between opposite monolayers of a membrane bilayer), and because of its small (and nonionic) head group, a negative curvature is made easier by an accumulation of cholesterol (see [42] for a review).

In view of all the above considerations concerning the roles of lipid head-group hydration, acyl chain length, and cholesterol content, the dispersed lipid particles of LCM/ND nanoemulsions very likely represent liquid-crystalline inverse-topology nanocarriers, i.e., dispersed lipid cubic phases (cf. [42]).

5. Serum Amyloid A (SAA), SR-BI, and Alzheimer's Disease

Various past studies indicate that inflammation plays an important role in the process of amyloid deposition and, therefore, inhibition of inflammatory cascades may attenuate amyloidogenic processes – such as Alzheimer's disease (e.g., [67]; cf. [68,69] ). Moreover, recent research indicates that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A from the gastrointestinal tract [cf. below] ) 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 [70,71]. ( Note too that unlike other acute phase proteins, which are synthesized primarily in the liver, acute-phase SAA is also markedly expressed at local sites of tissue inflammation. Furthermore, very recent work by other investigators suggest that brain injury can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes. For example, SAA can induce activation of the inflammasome in microglial cells and give rise to cytokine release which can exacerbate inflammation in the brain following neurological diseases [72,73,74].) 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.

Specifically, earlier research [75] 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. [76]). Accordingly, multiple studies suggest that SAA may have profound effects on innate immunity as a result of its chemotactic and cytokine-inducing activities [72]. 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 [75]. For example, it has already been documented repeatedly in the literature that both apo A-I and SAA are substrates for SR-BI, which indicates that SR-BI can mediate the transport of both proteins across the BBB (e.g., [77]). Not surprisingly, therefore, Robert et al. have recently asserted that many lines of evidence suggest a protective role regarding HDL and its major apolipoprotein (apo)A-I in Alzheimer's disease [17]. Accordingly, a similar benefit (of “competitive binding” to SR-BI receptors) may well accompany intravenous use clinically 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 Sect. 2].

6. Conclusions

The risk factors for Alzheimer's disease can all synergistically promote diverse pathological mechanisms. In particular, more recent research indicates that chronic inflammatory stimulus in the gut may induce (e.g., notably via serum amyloid A (SAA)) the release of proinflammatory cytokines. At the same time, increased BBB permeability due to aging and/or dysfunction, in turn, allows these proinflammatory cytokines to enter the brain, inducing glia reactivity. 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.


This research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors.

Competing Interests

The authors declare no conflict of interest. J.S.D. is employed at Cav-Con Inc.


  1. D'Arrigo JS. Alzheimer’s disease, brain injury, and CNS nanotherapy in humans: Sonoporation augmenting drug targeting. Med Sci. 2017; 5: 29. [CrossRef]
  2. D'Arrigo JS. Nanotherapy for Alzheimer’s disease and vascular dementia: Targeting senile endothelium. Adv Colloid Interface Sci. 2018; 251: 44-54. [CrossRef]
  3. D'Arrigo JS. Targeting early dementia: Using lipid cubic phase nanocarriers to cross the blood-brain barrier. Biomimetics. 2018; 3: 4. [CrossRef]
  4. D'Arrigo JS. Delaying dementia: Targeted brain delivery using lipid cubic phases. OBM Neurobiol. 2019; 3. doi: 21926/obm.neurobiol.1903040. [CrossRef]
  5. D'Arrigo JS. Naonotherapy to delay cognitive impairment: Using colloidal nanocarriers to block amyloid-beta-induced damage in brain cell membranes. SDRP J Nanotech Mat Sci. 2019; 2: 94-105. [CrossRef]
  6. D'Arrigo JS. Treating early dementia: Drug targeting and circumventing the blood-brain barrier. Geriatr Med Care. 2018; 3: 4. [CrossRef]
  7. 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]
  8. 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]
  9. Carradori D, Gaudin A, Brambilla D, Andrieux K. Application of nanomedicine to the CNS diseases. Int Rev Neurobiol. 2016; 130: 73-113. [CrossRef]
  10. Zenaro E, Piacentino G, Constantin G. The blood–brain barrier in Alzheimer’s disease. Neurobiol Dis. 2016; 107: 41-56. [CrossRef]
  11. 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]
  12. Koizumi K, Wang G, Park L. Endothelial dysfunction and amyloid-induced neurovascular alterations. Cell Mol Neurobiol. 2016; 36:155-165. [CrossRef]
  13. 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]
  14. 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]
  15. Fung KY,Wang C, Nyegaard S, Heit B, Fairn GD, LeeWL. SR-BI mediated transcytosis of HDL in brain microvascular endothelial cells is independent of caveolin, clathrin, and PDZK1. Front Physiol. 2017; 8: 841. [CrossRef]
  16. 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]
  17. Robert J, Stukas S, Button E, Cheng WH, Lee M, Fan J, et al. Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice. Biochim Biophys Acta. 2016; 1862: 1027-1036. [CrossRef]
  18. Hottman, DA, Chernick D, Cheng S, Wang Z, Li L. HDL and cognition in neurodegenerative disorders. Neurobiol Dis. 2014; 72: 22-36. [CrossRef]
  19. 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]
  20. 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]
  21. 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]
  22. McAleese KL, Alafuzoff I, Charidimou A, De Reuck J, Grinberg LT, Hainsworth AH, et al. Post-mortem assessment in vascular dementia: advances and aspirations. BMC Med. 2016; 14: 129. [CrossRef]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. Khalil RB, Khoury E, Koussa S. Linking multiple pathogenic pathways in Alzheimer’s disease. World J Psychiatry. 2016; 6: 208-214. [CrossRef]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. Kalaria, RN, Akinyemi R, Ihara M. Stroke injury, cognitive impairment and vascular dementia. Biochim Biophys Acta. 2016; 1862: 915-925. [CrossRef]
  37. Khan A, Kalaria RN, Corbett A, Ballard C. Update on vascular dementia. J Geriatr Psychiatry Neurol. 2016; 29: 281-301. [CrossRef]
  38. 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]
  39. 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]
  40. Wang YJ. Lessons from immunotherapy for Alzheimer’s disease. Nat Rev Neurol. 2014; 10: 188-189. [CrossRef]
  41. Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer’s disease. Nat Rev Neurol. 2013; 9: 25-34. [CrossRef]
  42. D'Arrigo JS. Stable Nanoemulsions: Self-Assembly in Nature and Nanomedicine. Amsterdam: Elsevier; 2011. 415 pp, ISBN 978-0-444-53798-0.
  43. 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]
  44. Garg G, Saraf Sh, Saraf Sw. Cubosomes: An overview. Biol Pharm Bull. 2007; 30: 350-353. [CrossRef]
  45. Pouton CW. Properties and uses of common formulation lipids, surfactants and cosurfactants. Proceedings of the AAPSWorkshop -- 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.
  46. 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]
  47. Small DM. The behavior of biological lipids. Pure Appl Chem. 1981; 53: 2095-2103. [CrossRef]
  48. Seddon JM, Robins J, Gulik-Krzywicki T, Delacroix H. Inverse micellar phases of phospholipids and glycolipids. Phys Chem Chem Phys. 2000; 2: 4485-4493. [CrossRef]
  49. 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]
  50. 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]
  51. 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.
  52. 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.
  53. D'Arrigo JS. Treating dementia early: Limiting cellular damage in brain tissue. OBM Geriatr. 2019; 3. doi:10.21926/obm.geriatr.1902057. [CrossRef]
  54. Schwarz US, Gompper G. Bending frustration of lipid-water mesophases based on cubic minimal surfaces. Langmuir. 2001; 17: 2084-2096. [CrossRef]
  55. Ces O, Mulet X. Physical coupling between lipids and proteins: A paradigm for cellular control. Signal Transduct. 2006; 6: 112-132. [CrossRef]
  56. Pouzot M, Mezzenga R, Leser M, Sagalowicz L, Guillot S, Glatter O. Structural and rheological investigation of Fd3m inverse micellar cubic phases. Langmuir. 2007; 23: 9618-9628. [CrossRef]
  57. 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]
  58. Seddon JM, Templer RH, Warrender NA, Huang G, Cevc G, Marsh D. Phosphatidylcholine-fatty acid membranes: Effects of headgroup hydration on the phase behaviour and structural parameters of the gel and inverse hexagonal (HII) phases. Biochim Biophys Acta. 1997; 1327: 131-147. [CrossRef]
  59. Huang Z, Seddon JM, Templer RH. An inverse micellar Fd3m cubic phase formed by hydrated phosphatidylcholine/fatty alcohol mixtures. Chem Phys Lipids. 1996; 82: 53-61. [CrossRef]
  60. Chen Z, Rand RP. The influence of cholesterol on phospholipid membrane curvature and bending elasticity. Biophys J. 1997; 73: 267-276. [CrossRef]
  61. Tilcock CPS, Hope MJ, Cullis PR. Influence of cholesterol esters of varying unsaturation on the polymorphic phase preferences of egg phosphatidylethanolamine. Chem Phys Lipids. 1984; 35: 363-370. [CrossRef]
  62. Cullis PR, De Kruijff B. Polymorphic phase behaviour of lipid mixtures as detected by 31P NMR: Evidence that cholesterol may destabilize bilayer structure in membrane systems containing phosphatidylethanolamine. Biochim Biophys Acta. 1978; 507: 201-218. [CrossRef]
  63. Noordam PC, van Echteld CJA, De Kruijff B, Verkleij AJ, de Gier J. Barrier characteristics of membrane model systems containing unsaturated phosphatidylethanolamine. Chem Phys Lipids. 1980; 27: 221-232. [CrossRef]
  64. Gallay J, De Kruijff B. Correlation between molecular shape and hexagonal HII phase promoting ability of sterols. FEBS Lett. 1982; 143: 133-136. [CrossRef]
  65. Simon SA, McIntosh TJ, Lattore R. Influence of cholesterol on water penetration into bilayers. Science. 1982; 216: 65-68. [CrossRef]
  66. Ohvo-Rekila H, Ramstedt B, Leppimaki P, Slotte JP. Cholesterol interactions with phospholipids in membranes. Prog Lipid Res. 2002; 41: 66-97. [CrossRef]
  67. Guo JT, Yu J, Grass D, de Beer FC, Kindy MS. Inflammation-dependent cerebral deposition of serum amyloid A protein in a mouse model of amyloidosis. J Neurosci. 2002; 22: 5900-5909. [CrossRef]
  68. Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017; 95: 943-972. [CrossRef]
  69. Birch AM, Katsouri L, Sastre M. Modulation of inflammation in transgenic models of Alzheimer's disease. J Inflammation. 2014; 11: 25. [CrossRef]
  70. Talwar P, Kushwaha S, Gupta R, Agarwal R. Systemic immune dyshomeostasis model and pathways in Alzheimer's disease. Front Aging Neurosci. 2019; 11: 290. [CrossRef]
  71. Osorio C, Kanukuntla T, Diaz E, Jafri N, Cummings M, Sfera A. The post-amyloid era in Alzheimer's disease: Trust your gut feeling. Front Aging Neurosci. 2019; 11: 143. [CrossRef]
  72. Baranova IN, Souza ACP, Bocharov AV, Vishnyakova TG, Hu X, Vaisman BL, et al. Human SR-BI mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo. PloS ONE. 2019; 12: e0175824. [CrossRef]
  73. Yu J, Zhu H, Taheri S, Mondy W, Bonilha L, Magwood GS, et al. Serum amyloid A-mediated inflammasome activation of microglial cells in cerebral ischemia. J Neurosci. 2019; 39: 9465-9476. [CrossRef]
  74. Walker KA, Ficek BN, Westbrook R. Understanding the role of systemic inflammation in Alzheimer's disease. ACS Chem Neurosci. 2019; 10: 3340-3342. [CrossRef]
  75. Baranova IN, Vishnyakova TG, Bocharov AV, Kurlander R, Chen Z, Kimelman ML, et al. Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases. J Biol Chem. 2005; 280: 8031-8040. [CrossRef]
  76. Mullan RH, McCormick J, Connolly M, Bresnihan B, Veale DJ, Fearon U. A role for the high-density lipoprotein receptor SR-BI in synovial inflammation via serum amyloid-A. Am J Pathol. 2010; 176: 1999-2008. [CrossRef]
  77. Erickson MA, Jude J, Zhao H, Rhea EM, Salameh TS, Jester W, et al. Serum amyloid A: An ozone-induced circulating factor with potentially important functions in the lung-brain axis. FASEB J. 2017; 31: 3950-3965 [CrossRef]
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