A New Perspective for the Treatment of Alzheimer’s Disease: Exosome-like Liposomes to Deliver Natural Compounds and RNA Therapies
Abstract
:1. Introduction
2. Neurodegenerative Diseases
- Tau protein—microtubule-associated protein—encoded by the microtubule-associated protein tau (MAPT) gene. Tau is substantially expressed in the cytoplasm of neurons and plays an important role primarily in the stabilization and assembly of axonal microtubules and also in a variety of physiological processes, which include axonal transport, signal transmission between neurons, neurogenesis, myelination, motor function, neuronal excitability, glucose metabolism, iron homeostasis, and DNA protection [15,16].
- Aβ—derives from the amyloid precursor protein (APP) and aggregates into amyloid plaques with Aβ polypeptides 40 and 42 amino acids long [17].
- Prion—another protein present in neurodegenerative diseases is the prion protein (PrP) encoded by the PRNP gene. In prion diseases, the prion protein misfolds, propagates, and aggregates rapidly, being responsible for spreading neurodegeneration between cells, and, consequently, brain regions [14].
- α-synuclein—this is a 140-amino-acid protein highly expressed in the brain, encoded by the α-synuclein (SCNA) gene [12].
Alzheimer’s Disease
3. Natural Compounds for AD Treatment
Overcoming Limitations of Natural Compounds with Delivery Systems
4. RNAs as a Promising Tool in the Treatment of AD
- miRNA
- siRNA
- mRNA
Role in AD | References | |
---|---|---|
Types of miRNA | ||
miR-101 | Significantly reduced the expression of a reporter under control of APP 3′-UTR in HeLa cells. | [95] |
miR-106b | Overexpression of miR-106b inhibited Aβ1-42-induced tau phosphorylation at Tyr18 in SH-SY5Y cells stably expressing Tau. | [96] |
miR-137 | miR-137 inhibited increased expression levels of p-tau induced by Aβ1-42 in SH-SY5Y and inhibited the hyperphosphorylation of Tau protein in a transgenic mouse model of AD. | [97] |
miR-219 | In a Drosophila model that produces human Tau, reduction of miR-219 exacerbated Tau toxicity, while overexpression of miR-219 partially annulled toxic effects. | [98] |
miR-17 | miR-17 inhibits elevated miR-17 in adult AD (5xFAD) mice microglia improves Aβ degradation. | [99] |
miR-20b-5p | Treatment with miR-20b-5p reduced APP mRNA and protein levels in cultured human neuronal cells. | [100] |
miR-29c | Over-expression of miR-29c in SH-SY5Y, HEK-293T cell lines and miR-29c in transgenic mice downregulated BACE1 protein levels. | [101] |
miR-298 | miR-298 is a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Thus, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the Tau protein without significant alterations of total Tau or other forms. | [102] |
miR-485-5p | miR-485-5p overexpression facilitated the learning and memory capabilities of APP/PS1 mice and promoted pericyte viability and prohibited pericyte apoptosis in this model. | [103] |
miR-9-5p | miR-9-5p overexpression inhibited Aβ25-35-induced mitochondrial dysfunction, cell apoptosis, and oxidative stress by regulating GSK-3β expression in HT22 cells. | [104] |
miR-132 | miR-132 inhibited hippocampal iNOS expression and oxidative stress by inhibiting MAPK1 expression to improve the cognitive function of rats with AD. | [105] |
miR-153 | Using miR-153 transgenic mouse model, was verified that miR-153 downregulated the expression of APP and APLP2 protein in vivo. | [106] |
Targeted gene silencing by siRNA | ||
Tau | siRNA against MAPT can effectively suppress tau expression in vitro and in vivo without a specific delivery agent. | [107] |
BACE1 | Polymeric siRNA nanomedicine targeting BACE1 in APP/PS1 transgenic AD mouse model can efficiently penetrate the BBB via glycemia-controlled glucose transporter-1–mediated transport, ensuring that siRNAs decrease BACE1 expression. | [94] |
Presenilin1 (PS1) | Downregulation of PS1 and Aβ42 in IMR32 cells transfected with siRNA against PS1 was verified. | [108] |
APP | Infusion of siRNAs that down-regulated mouse APP protein levels into the ventricular system for 2 weeks down-regulated APP mRNA in mouse brain. | [109] |
Proteins encoded by mRNA | ||
mRNA encoding neprilysin | Neprilysin plays a major role in the clearance of Aβ in the brain. New mRNA therapeutic strategy utilizing mRNA encoding the mouse neprilysin protein has been shown to decrease Aβ deposition and prevent pathogenic changes in the brain. | [110] |
Overcoming Limitations of RNA Therapies with Delivery Systems
5. Nanoparticles and the BBB
5.1. Exosomes
5.2. Liposomes
5.3. Exosome-like Liposomes as a Novel Strategy
- Dendrimers: Dendrimers are highly branched, characterized by defined molecular weights and specific encapsulation properties. This type of delivery system is composed of symmetrical polymeric macromolecules with a large number of reactive surface groups, with three distinctive architectural components: An interior core, an interior layer consisting of repeating units radially attached to the inner core, and functional end groups on the outside layer. Because of these unique features, dendrimers can cross-impair the BBB and target astrocytes and microglia after systemic administration in animal models [139].
- Polymeric nanoparticles: Polymeric nanoparticles can be produced from synthetic or natural polymers. However, to be applied in brain drug delivery, these nanoparticles need to be biodegradable and biocompatible. PBCA, PLA, and PLGA nanoparticles are nanoparticles able to cross the BBB. These nanocarriers possess controlled drug release, targeting efficiency, and can avoid phagocytosis by the reticuloendothelial system, thus improving the concentration of drugs in the brain [140].
- Gold nanoparticles: Nanoparticles (mostly < 10 nm in size) composed of a gold core and with covalently or non-covalently attached surface ligands. Multiple in vivo studies on rodents have shown that low amounts of this delivery system were able to cross the BBB. However, greater amounts of the administered dose were found in the liver and in the blood [8]. Additionally, Sela et al. proved that gold nanoparticles could penetrate the BBB of rats without the use of an external field or surface modification and were found to be distributed uniformly in both the hypothalamus and hippocampus indicating there is no selective binding in these regions of the brain [141].
- Carbon quantum dots: This delivery system retains a polymeric core structure and various functional groups on the surface, facilitating their conjugation with drug molecules for specific delivery. This is a carrier with several efficient features for BBB crossing such as excellent biocompatibility and low toxicity due to the lack of metal elements, small size, and photoluminescence, which can be utilized to track the penetration of CDs through the BBB [117].
6. Conclusions
7. Patents
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Natural Compound | Role in AD | References |
---|---|---|
Eugenol | Rats were fed aluminum, a neurotoxic metal that leads to oxidative brain injury and enhanced lipid peroxidation, disruption of neurotrophic, cholinergic, and serotonergic functions, and induce apoptosis with ultimate neuronal and astrocyte damages. A neuroprotective role of eugenol against the aluminum effects was verified through its antioxidant, antiapoptotic potential and its neurotrophic properties. | [51] |
Menthol | Menthol inhalation by mice (1 week per month, for 6 months) prevented cognitive impairment in the APP/PS1 mouse model of Alzheimer’s. | [52] |
Chrysin | Chrysin showed the ability to act as a membrane shield against early oxidative events mediated by O2˙- and other ROS that contribute to neuronal death triggered by AlCl3 exposure, showing chrysin’s neuroprotective action. | [53] |
Rosmarinic acid | Suppresses Aβ accumulation in mice. | [54] |
Ginkgo biloba | Ginkgo biloba improves microcirculation, inhibits the expression of inflammatory factors, and reduces inflammatory damage to neurons, thereby improving the spatial exploration memory of dementia model rats. | [55] |
Resveratrol | Multiple studies demonstrated that resveratrol has neuroprotective, anti-inflammatory, and antioxidant characteristics and the ability to minimize Aβ peptide aggregation and toxicity in the hippocampus of Alzheimer’s patients, stimulating neurogenesis and inhibiting hippocampal degeneration. Furthermore, resveratrol’s antioxidant effect promotes neuronal development by activating the silent information regulator-1, which can protect against the detrimental effects of oxidative stress. | [56] |
Huperzine A | Huperzine A is natural, potent, highly specific reversible inhibitor of acetylcholinesterase, with the ability to cross the BBB. | [57] |
Brahmi | The neuroprotective properties of Brahmi include the reduction of ROS and neuroinflammation, the inhibition of the aggregation of Aβ and the improvement of cognitive and learning behavior. | [58] |
Uncaria tomentosa | Inhibits plaques and tangles formation. | [59] |
Berberine | Berberine has antioxidant activity and promotes AChE and monoamine oxidase inhibition. Berberine has been shown to improve memory, lower Aβ and APP concentration, and diminish Aβ plaque accumulation. | [60] |
Quercetin | Behavioral and biochemical tests confirm that quercetin promotes the reduction in oxidative stress and increased cognition in zebrafish AD models induced with aluminum chloride. | [61] |
Betaine | Betaine has been shown to decrease homocysteine levels and Aβ toxicity in Caenorhabditis elegans AD model. | [62] |
Curcumin | Curcumin is known to be a potent antioxidant, anti-inflammatory and anti-amyloidogenic compound, that plays a beneficial role in treating AD through several mechanisms. Curcumin can promote a significant reduction of Aβ oligomers and fibril formation. | [46] |
Crocin | Crocin, the main constituent of Crocus sativus L., has a multifunctional role in protecting brain cells, modulating aggregation of Aβ and Tau proteins, attenuating cognitive and memory impairments, and improving oxidative stress. | [63] |
Withania somnifera | Withania somnifera extract can protect against Aβ peptide- and acrolein-induced toxicity. Treatment with this extract significantly protected against Aβ and acrolein, in various cell survival assays with the human neuroblastoma cell line SK-N-SH, significantly reduced the generation of ROS and was demonstrated to be a potent inhibitor of AChE activity. | [64] |
Poncirus trifoliate | The extract of Poncirus trifoliate is a naturally occurring AChE inhibitor. It showed a 47.31% inhibitory effect on the activity of acetylcholine. | [65] |
Convolvulus pluricaulis | Convolvulus pluricaulis prevented aluminum-induced neurotoxicity in rat cerebral cortex. | [66] |
α-Cyperone | α-Cyperone binds and interacts with tubulin, being capable of destabilizing microtubule polymerization. The effect of this interaction could result in reduction of inflammation. | [67] |
Andrographolide | Andrographolide has beneficial effects in the recovery of spatial memory and learning performance, recovery of synaptic basal transmission, partial or complete protection of certain synaptic proteins and shows a specific neuroprotective effect, that includes the reduction of phosphorylated Tau and Aβ aggregate maturation, in aged degus. | [68] |
Apigenin | Apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models. This compound is also able to protect human induced pluripotent stem cell-derived AD neurons via multiple pathways, by reducing the frequency of spontaneous Ca2+ signals and significantly reducing caspase-3/7 mediated apoptosis. | [69] |
Baicalein | Baicalein has antioxidant and anti-inflammatory effects. | [70] |
Carvacrol | Carvacrol possesses anti-AChE, antioxidant, and neuroprotective properties. This compound alleviated Aβ-induced deficits by reducing cellular neurotoxicity and oxidative stress in the SH-SY5Y cell line, and by reducing oxidative stress and memory impairment in a rat model of AD. | [71] |
Decursin/Decursinol angelate | Decursin and decursinol angelate increase cellular resistance to Aβ-induced oxidative injury in PC12 cells. | [72] |
Genistein | In vivo studies have shown that genistein improves brain function, antagonizes the toxicity of Aβ and has neuroprotective effects. | [73] |
Wogonin | Wogonin has various neuroprotective and neurotrophic activities, such as inducing neurite outgrowth. | [74] |
Rutin | Rutin is antioxidant, anti-inflammatory, and has the capacity of reducing Aβ oligomer activities. | [75] |
Luteolin | Luteolin has the capacity to cross the BBB and can inhibit β- and γ-secretase to decrease Aβ. It can also reduce neuroinflammation and attenuate the phosphorylation of Tau. | [76] |
Linalool | A linalool-treated mice model of AD showed improved learning and spatial memory. This compound reverses the histopathological hallmarks of AD and restores cognitive and emotional functions via an anti-inflammatory effect. | [77] |
Asiatic acid | Pre-treatment with Asiatic Acid enhanced cell viability, attenuated rotenone-induced ROS, mitochondrial membrane dysfunction and apoptosis regulating AKT/GSK-3β signaling pathway, after aluminum maltolate neurotoxicity induction in SH-SY5Y neuroblastoma cells. | [78] |
Exosome-like Liposomes Applications | References |
---|---|
Exosome mimetics-mediated gene-activated matrix encapsulating the plasmid of vascular endothelial growth factor (VEGF) was able to sustainably deliver VEGF gene and significantly enhance the vascularized osteogenesis in vivo. | [145] |
PSMA-exosome mimetics showed increased cellular internalization in PSMA-positive PC cell lines (LNCaP and C4-2B) and higher tumor targeting was observed in solid C4-2B tumors, following intravenous administration, confirming their targeting ability in vivo. | [146] |
Exosome mimetics are reported for bone targeting involving the introduction of hydroxyapatite-binding moieties through bioorthogonal functionalization. Bone-binding ability of the engineered exosome mimetics is verified with hydroxyapatite-coated scaffolds and an ex vivo bone-binding assay. | [147] |
Administration of mesenchymal stem cells-exosome mimetics in conjunction with an injectable chitosan hydrogel into mouse nonhealing calvarial defects demonstrated robust bone regeneration. | [148] |
Bone marrow mesenchymal stem cells were sequentially extruded to generate exosome-mimetic to encapsulate doxorubicin to treat osteosarcoma. The results showed that demonstrated significantly more potent tumor inhibition activity and fewer side effects than free doxorubicin. | [149] |
In vitro, chemotherapeutic drug-loaded exosome-mimetics induced TNF-R-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded exosome-mimetics traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. | [150] |
Multifunctional exosomes-mimetics decorated with angiopep-2 (Ang-EM) incorporating Docetaxel, for enhancing glioblastoma drug delivery by manipulating protein corona, Ang-EM showed enhanced BBB penetration ability and targeting ability to the gioblastoma. Ang-EM-mediated delivery increased the concentration of docetaxel in the tumor area. | [151] |
A designed lung-targeting liposomal nanovesicle carrying miR-29a-3p that mimics the exosomes, significantly down-regulated collagen I secretion by lung fibroblasts in vivo, thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells. | [152] |
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Ribeiro, J.; Lopes, I.; Gomes, A.C. A New Perspective for the Treatment of Alzheimer’s Disease: Exosome-like Liposomes to Deliver Natural Compounds and RNA Therapies. Molecules 2023, 28, 6015. https://doi.org/10.3390/molecules28166015
Ribeiro J, Lopes I, Gomes AC. A New Perspective for the Treatment of Alzheimer’s Disease: Exosome-like Liposomes to Deliver Natural Compounds and RNA Therapies. Molecules. 2023; 28(16):6015. https://doi.org/10.3390/molecules28166015
Chicago/Turabian StyleRibeiro, Joana, Ivo Lopes, and Andreia Castro Gomes. 2023. "A New Perspective for the Treatment of Alzheimer’s Disease: Exosome-like Liposomes to Deliver Natural Compounds and RNA Therapies" Molecules 28, no. 16: 6015. https://doi.org/10.3390/molecules28166015
APA StyleRibeiro, J., Lopes, I., & Gomes, A. C. (2023). A New Perspective for the Treatment of Alzheimer’s Disease: Exosome-like Liposomes to Deliver Natural Compounds and RNA Therapies. Molecules, 28(16), 6015. https://doi.org/10.3390/molecules28166015