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Alzheimer's disease (AD) is an irreversible neurodegenerative disorder of the elderly characterized by progressive intellectual deterioration involving memory, language, and judgment, ultimately leading to total dependence on nursing care. More than 100 million people worldwide will be living with dementia by 2050, [1] with an estimated cost to reach $1 trillion by next year. [2] AD is the leading cause of dementia, and the possibility of developing AD roughly doubles every five years after 65, and it is close to 50% over the age of 85. [3,4] The major hallmark features of AD include the extracellular deposition of beta-amyloid (Aβ) plaques, the intraneuronal accumulation of neurofibrillary tangles (NFT) due to hyperphosphorylated tau, loss of synapses and neurons, vascular abnormalities, glial dysfunctions and neuroinflammation. [5][6][7][8] Although plaques and tangles are the major constituents in AD, there is no compelling evidence that the neurodegenerative process in AD begins in synapses. For example, the extent of synaptic loss, which begins prior to the appearance of tangles, plaques, or neuronal loss is an excellent correlate J o u r n a l P r e -p r o o f of dementia. [9][10][11] While the mechanism of neuropathology and the genetic basis of familial cases of AD (FAD) have been fairly understood, the molecular basis for sporadic cases of late-onset-AD (LOAD) which comprises the majority cases of AD is far from clear. Inheritance of two apolipoprotein E (APOE) ε4 alleles (APOE ɛ4/ɛ4) is the single most significant genetic risk factor for the development of LOAD, [12] and sixty percent of all AD patients carry at least one APOE ε4 allele. [13] More recent studies have identified a large number of other genetic risk alleles [14][15][16], implying that AD is a complex and highly heterogeneous disease. Amyloid plaques are parenchymal deposits of Aβ, a fibrillous 4-kDa protein of 40 to 43 amino acids derived from amyloid precursor protein (APP) by the sequential actions of β-and γsecretases at the N-and C-terminus of the Aβ domain, respectively. [17] FAD mutations are known to increase the generation of Aβ or produce more aggregation-prone Aβ. The oligomerization of excess Aβ leads to the plaque formation that causes neuronal cell death via intracellular neurofibrillary tangle formation and synaptic dysfunction leading to the loss of cognitive functions. [5][6][7][8][9][10][11] The abnormal hyperphosphorylation of a microtubule-associated tau protein (P-tau) has also been implicated in the AD pathogenesis. The P-tau proteins produce neurofibrillary tangles, neuropil threads, and neurotic plaques, which are surrounded by dystrophic neurites, that lead to AD development. [18] The elevated levels of both Aβ-42 and P-tau proteins in cerebrospinal fluid (CSF) are two excellent biomarkers that distinguish AD from other neurodegenerative diseases.
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Tau protein is phosphorylated either at threonine 231 (P-tau231P) or serine 199 (P-tau199P), with P-tau231P being the dominant form associated with the higher risk of Alzheimer's dementia. [19] Acetylcholine (ACh) is an essential neurotransmitter in the central and peripheral nervous systems. The elevated levels of acetylcholinesterase (AChE) reduce the ACh concentration and J o u r n a l P r e -p r o o f contribute to AD. There are several regions in the brain, including basal forebrain, where the cholinergic neurons are innervated. [20] The loss or degeneration of the cholinergic neurons in the basal forebrain, strongly intercorrelate with Aβ deposition and plaque formation, at the early stages of AD. The upregulation of AChE in mild AD condition does not affect the cholinergic forebrain neurons, but the loss of calcium-binding proteins (calbindin) in basal cholinergic forebrain induces the formation of tangles and severe functional alterations in cholinergic neurons. The severe functional impairment in the cholinergic neuronal axon reduces the neurotransmitter ACh and its biosynthetic enzyme choline acetyltransferase or ChAT. [21] There is a strong correlation between the AChE levels and the amyloid tangle formation. Therefore, blocking AChE activity has been proposed as one of the strategies to treat the cognitive impairment of AD patients.
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The neurotoxic accumulation of reactive oxygen species (ROS) has also been identified as a possible pathogenic mechanism for AD development. ROS, such as hydrogen peroxide, superoxide anions, and hydroxyl radicals, cause mitochondrial dysfunction, and cell death. [22][23][24] The brain consumes 20% more oxygen than any other tissue, which makes it more susceptible to the potential damage by ROS. The APP is expressed in higher quantities when the brain attempts to repair the oxidative damage caused by ROS, which in the case of AD, leads to the production and accumulation of Aβ plaques. [25][26][27] This leads to a higher production of superoxide anions, which diminishes the oxidative phosphorylation and the cellular ATP pool causing mitochondrial dysfunction and further development and severity of AD.
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Numerous treatment modalities and therapeutics have been developed to target the abovedescribed AD pathologies, i.e., Aβ aggregation, P-tau protein, ROS, and AChE inhibitions. [28,29] Recent studies have proposed the utility of tacrine, estradiol, curcumin, and peptides, including D-peptide in AD treatment. [30][31][32][33] However, the above potential therapeutics have been limited
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J o u r n a l P r e -p r o o f due to the poor permeability of the blood-brain barrier (BBB) and side effects of subacute myelopathic neuropathy (SMON). [22,34] Nano-delivery is a superior alternative due to the sitespecific delivery, ability to cross the BBB, enhanced drug solubility, and higher therapeutic efficacy. Nanoparticles (NPs) used for drug encapsulation, which increases the drug half-life and sustained-release while extending further bioavailability in the brain. [35,36] The capacity of multiple drug loading onto NPs also improves the therapeutic efficacy. Furthermore, the ability to tag a site-specific ligand enhances the accumulation of drugs at the specific tissue region and the drugs' ability to cross the BBB. [37][38][39] NPs thus play a significant role in providing better treatment options for AD, and this review discusses the different types of NPs which have been exploited to develop the AD treatments in the field of targeted drug delivery.
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NPs are materials that lay on the 1-100 nm scale. The numerous organic and inorganic materials can be used to synthesize NPs. NPs are popular as nanocarriers, mainly due to their characteristics such as high water dispersity, biocompatibility, and biodegradability. [40][41][42] Most of the drugs that target AD have low bioavailability and lack of ability to cross BBB. Therefore, NPs are mostly the best candidates to deliver drugs to the brain that can improve the drugs' bioavailability and half-life even at a lower concentration. NPs also enhance the efficacy of therapeutics by increasing the target specificity, via reducing the acute toxicity. [43][44][45] There are varieties of nanoparticles that have been used in AD studies. The most popular nano-agents are liposomal and polymeric NPs, while metallic, carbon-based, and curcumin NPs have also been studied. Therefore, this review article focuses on NPs' participation in different pathogenesis of AD.
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Liposomal NPs were introduced in 1965, which was the first NP used as a nano-drug carrier.
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Liposomes are spherical-shaped vesicles which have an aqueous inner core and vesicle shell. They consist of the single or bilayered lipid membrane structure. [46,47] The amphiphilicity of the J o u r n a l P r e -p r o o f phospholipid molecules in lipid vesicles make liposomes amphiphilic. The impressing fact is, not all the lipid or phospholipid combinations in the nanoscale make liposomes. Some nano-scale phospholipids combinations have different shapes, such as hexagonal, micellar, or cubic phases, making them deviate from the liposomal characteristics, wherein only the vesicle spheres have the liposomal NPs features. [48] Liposomes are highly biodegradable, non-toxic, and nonimmunogenic. [47,49] The size distribution of liposomal NPs is broad as 10 nm-10 µm. Liposomal
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NPs can encapsulate hydrophilic agents in their hydrophilic cores and hydrophobic agents in their hydrophobic membranes. The versatile structure of liposomal NPs makes them easy to load probes and therapeutic agents, which also facilitate BBB penetration. Liposomal NPs can be synthesized by using many different natural sources such as milk, soy, eggs, and even the very first natural food, breast milk. [50][51][52] These natural sources are enriched with phospholipids and lipid vesicles, which provide liver protection and memory improvement as health welfares to liposomal NPs. [53][54][55] Therefore, liposomal NPs are one of the best candidates to be used in AD drug delivery systems.
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Due to the broadness of AD, liposomes have been applied to target numerous AD pathogenesis.
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Masserini and co-workers have designed amphipathic liposomal NPs, to target the gangliosides of the Alzheimer's brain while showed a higher affinity to Aβ1-42 peptide and lysosomes. [56][57][58] Liposomal NPs were made up of a 1:1 molar ratio of sphingomyelin (Sm) and cholesterol mixed Even though the SPR results suggested that the PA, CL, and ganglioside liposomes showed the best affinity towards Aβ1-42, the results have not been further proved by in vivo or in vitro studies. [56] Authors have also confirmed the cell-permeability of their large size liposomal NPs by using those as bio-imaging probes that are conjugated with cell-permeant dye calcein. The conjugated system displayed green fluorescence due to the acetoxymethyl ester hydrolysis after the interaction with intracellular esterases, which proved the successful cell membrane penetration of the liposomal conjugated system. [56] However, the authors suggested that their results are open to the public to develop better nanocarrier for imaging and drug delivery in AD studies. Therefore, based on the above research, Balducci et al. designed a receptor-mediated liposomal model of bifunctionalized liposome, mApoE-PA-Lip, by using mApoE peptide (which derived from apolipoprotein-E) and phosphatidic acid (PA). [59] The mApoE peptide is the BBB binding ligand, and phosphatidic acid directs the NP system to Aβ binding domain. The overall particle size after the conjugation was approximately 120 nm and the zeta potential was -18.7 mV. The in vitro studies were conducted with synthetic Aβ1-42 fibrils in phosphate buffer solution. The electron microscopic images have shown the ability of liposome conjugate to disaggregate and delay the formation of Aβ deposits. The in vivo studies were performed by 10 months old APP/presenilin 1 transgenic mice (Fig. 1). The mice were injected with mApoE-PA-LIP for three times (once a week) before the histological analysis. The results have displayed, the reduction of brain soluble Aβ1-42 by 33% and the total plaques by 34%. The PET imaging studies conducted with APP23 mice have revealed the depletion of Aβ deposits after the treatments of bifunctionalized liposomes, mApoE-PA-LIP. Therefore, the authors concluded saying the mApoE-PA-LIP showed the J o u r n a l P r e -p r o o f superiority by crossing BBB, interacting with the AD brain region, and diminishing the Aβ aggregates. The depletion of Aβ was stable for more than 3 months of period (Fig. 2). .32 mV of zeta potential. [60] The principal goal of their study is to identify the type of Aβ that capable of crossing the endothelial cells in the transwell BBB model to be in the equilibrium of the brain and blood side. Their control experiment stated that only the small soluble Aβ oligomers spontaneously crossed the endothelial monolayer, but not the Aβ fibrils. In the presence of liposomal conjugation of mApoE-PA-LIP, the concentration of Aβ oligomers was enhanced 5fold in the apical compartment (which mimics the blood side) in the transwell model compared to the basolateral compartment (which mimics the brain side). Authors verified the higher permeability of Aβ oligomers into the blood is due to the higher binding affinity of Aβ oligomers with mApoE-PA-LIP. However, the authors are not capable of ascertaining the permeability of Aβ fibrils from the brain side to the blood side by their transwell model. publishers. Zheng et al. introduced H102 (HKQLPFFEED) peptide-loaded liposomes to deliver drugs for the AD treatments.[64] The mean particle size of the peptide loaded-liposomes was 112.2 nm with a narrow distribution range. The zeta potential was -2.96 mV, and the peptide loading ability on liposomes was 71.35%. The secondary structure formation of the peptide was analyzed by circular showed lower absorption rate and longer retention time compared to free H102, suggesting liposome bound H102 as a superior candidate to deliver drugs. The brain uptake study further proved that no drug was found in the brain after the intravenous administration of the liposome bound H102, verifying the incapability of BBB penetration. The intranasal administration has shown a better absorption in the brains' olfactory bulb region, proving the intranasal administration is the best method to deliver drugs with H102 bound liposomes. Moreover, the authors reported that the liposomal bound H102 and free H102 could protect the central cholinergic neurons, by reducing the AchE levels and enhancing the ChAT to upregulate the ACh secretion to diminish the cognitive impairment.
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Polymeric NPs fall into two categories, such as natural and synthetic NPs. Chitosan and cellulosebased polymeric NPs are the natural formers, while synthetic polymeric NPs are usually made up of binding copolymers into another polymer matrix. [65] Chemical synthesis of polymeric NPs can be achieved by emulsification, salting out, and nanoprecipitation. [66,67] The particle sizes of chitosan and synthetic polymers range from 50 to a few hundred nanometers. Drugs or any ligands
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Synthetic polymeric NPs are colloidal particles, which can be further altered to tune the lipophilicity, charge, and biocompatibility during the synthetic process. [84] The high water solubility and cell permeability make polymeric NPs stable over a long period, even during the gradual release of the loaded drugs. Polymeric NPs have high drug loading capacity as well as low toxicity. Especially when they were coated with polyethylene glycol (PEG)-phospholipid copolymers, the toxicity could be reduced. Polyhydroxyalkanoates, polylactide-co-glycolide (PLGA), cyclodextrin-derived, and PEG-coated polymeric NPs are vastly applied as nanocarriers The mean particle size of the gene and peptide conjugated NPs was 97 nm, and the zeta potential
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Metallic NPs can be synthesized basically from any metal and some metal oxides by obtaining different sizes, shapes, surface functionalization, structures, optical, and electronic properties. [98,99] Most commonly, silver, copper, gold, platinum, iron, and iron oxides (Fe3O4) are used as metallic NPs. Metallic NPs have remarkable physical and chemical properties that are different from the bulk materials, such as wavelength-dependent photoluminescence (PL), smaller size, high water dispersity, and localized surface plasmon resonance. [99,100] Vastly different fields use the benefits of metallic NPs such as electronic applications as catalysts, biomedical fields as nano-DDS in vitro and in vivo, and as enzymatic biosensors. [98] The biggest downside of the metallic NPs is the elevated toxicity at higher concentrations. There is a tendency to change the metallic NPs structure into toxic structures with the touch of chemicals in the synthesis process that ultimately leads to excrete and accumulate in the tissues during the in vivo applications, making it toxic to use for animal studies. However, gold NPs (AuNPs) and iron oxide NPs have been widely used as metallic NPs in AD studies.
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The most applicable metallic NP in every field is AuNP. AuNPs have drastic differences from its bulk material. Bulk gold is a yellow solid, which is inert, whereas the the colloidal solution of AuNPs is wine red, which acts as an anti-oxidant. [101] AuNPs are more popular compared to other metal-based NPs because of its' unique properties such as shape, size-dependent optical properties, the interaction of the Aβ1-16 peptide with metallic ions of Ca 2+ and Zn 2+ . [112] The molecular events of AuNPs can be easily observed qualitatively by its' color changes, which can be further analyzed analytically by the absorption spectrum and surface plasmon resonance (SPR). The main ADrelated peptide Aβ1-42 has 42 amino acids that undergo conformational changes into amyloid-like aggregates of Aβ1-16, which bind with metal ions to generate cell toxicity. [113,114] Therefore, Wang et al. synthesized Aβ1-16 conjugated AuNPs to study the interaction with Ca 2+ and Zn 2+ . [112] The color of Aβ1-16 bound AuNPs had changed from red to purple when it was interacted with Zn 2+ . The SPR band was red-shifted from 527 to 537 nm, with the increment of Zn 2+ concentration.
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Also, the results further confirmed that Ca AChE to the medium while displaying the new two peaks at 600 and 800 nm, revealing the desorption of RB from the AuNP surface (Fig. 7 a). Also, the authors further stated the AChE detection limit by RB-AuNPs was much lower (0.1 mU mL -1 ) than the previously reported values.
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Thus, the authors suggested that the RB-AuNPs assays could be useful to detect AChE levels in human AD brains. However, as described above, Ray and co-workers, and Wang and Liu et al., have only used AuNPs as sensors. AuNPs have also been used in quantitative AD studies, such as Aβ inhibitions. The inhibition of Aβ fibrillation and the initiation of its' alteration have been studied by Liao et al. by using bare AuNPs in the Aβ1-40 peptide model system.[116] Negatively and positively
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In addition to AuNPs, some other metal-based NPs, such as iron, copper, and zinc, are used in AD treatments as metal-ion detection chelators. The widely used magnetic NP is Fe3O4. [117] The magnetic NP of Fe3O4 has been commonly used in AD studies to detect the metal ions Cu 2+ and Zn 2+ that accelerate the ROS formation and Aβ aggregation.
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In 2012 Li et al. have synthesized magnetic Fe3O4 caged NPs to use as a photolytic controlled release-prochelator (CQ). [118] The photoactive molecules were covalently conjugated to the Fe3O4 caged NP surface, followed by the direct substitution of CQ molecules onto the surface. The loading quantity of the CQ molecules was calculated by thermogravimetric and elemental analyses. The relative immobilization efficiency was 56.96 µmol g -1 Fe3O4 NPs. The maximum release of the CQ molecules from the NPs surface was 30% at 3 min. The metal ion chelation of the photo-released product of CQ, with Cu 2+ , was tested by UV-vis spectroscopy. CQ showed a peak at 335 nm in the UV-vis spectroscopic data, whereas after the Cu 2+ addition, a new peak appeared at 410 nm corresponding to the copper complex. The controlled experiment was carried out in the dark, which shows no peak appeared at 410 nm, confirming the light-triggered release of CQ molecules. The effect of the photolytic product of CQ on Cu 2+ induced Aβ aggregation was J o u r n a l P r e -p r o o f conducted in a weak acidic buffer solution, by based on the previous studies that have reported as the Cu 2+ induced Aβ aggregation was more prominent at pH 6.6. [114,119] Aβ aggregates were incubated with Fe3O4 NPs in dark or light irradiated conditions. Before the irradiation, the Aβ amorphous aggregates were 10-15 nm in size, while after the irradiation, fewer aggregates with smaller size were found. The samples incubated in the dark showed no change in the size of Aβmetal aggregates. Therefore, the results concluded the effectiveness of light-sensitive magnetic NPs in inhibiting the Aβ aggregation.
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Not only the Aβ cascade but the tracking of senile plaques is also equally important, and it was the first step of AD treatments in the early stages. However, the used pathological staining dyes, including chrysamine C, congo red, and styryl benzene, failed to cross BBB. to bind with senile plaques and for the MRI studies that able to use as a contrasting agent as well as a good BBB crossing agent.
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Besides using magnetic NPs as metal ion chelators or imaging probes, it was also used as tau protein detecting sensors. Most of the nanosensors have been developed to detect only β amyloids, not to identify the phosphorylated tau proteins. The clinical studies have shown that abnormally low levels of Aβ and tau proteins are present in early-stage AD brain plasma, indicating the need for ultra-sensitive probes. [122][123][124][125][126] Upon this need, Ray and co-workers have developed large scale chemically stable magnetic plasmonic nanoplatforms to separate and quantify the trace levels of β-amyloid and tau proteins in the whole blood samples. [127] The conjugation of magnetic Fe3O4 with gold plasmonic shell NPs was followed by the bioconjugation of the 2D graphene oxide.
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Furthermore, the hybrid graphene oxide was coated with amine-modified polyethylene glycol (HS-PEG) and conjugated with anti-amyloid and anti-tau antibodies. According to the ELISA experiment, the displayed high efficiencies for NP conjugated-anti-amyloid and anti-tau antibodies at the lowest concentration of 100 fg/mL are 98 and 97%, respectively. The authors further reported that this detection limit is lower than the regular ELISA kit detection of Aβ (0.312 ng/mL) and tau proteins (0.15 ng/mL), which makes their NP system is more sensitive to detect Aβ1-42 and tau proteins.
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So far, as described above, the most popular magnetic NP was Fe3O4 that has been used as metal ion detectors, imaging probes, and sensors. Besides Fe3O4 magnetic NP, ceria NP has also been used in AD-related studies as reactive oxygen species (ROS) scavengers. The ROS, such as superoxide anions, hydroxyl radicals, and hydrogen peroxides, cause mitochondrial dysfunction, contributing to AD pathogenesis. [23,128] ROS arise in the mitochondria as a byproduct of oxidative phosphorylation, and interact with Aβ peptides and the mitochondrial proteins of alcohol J o u r n a l P r e -p r o o f dehydrogenase, cyclophilin D, and ATP synthase to increase the Aβ production in the brain. [129][130][131][132] Therefore, the detection of ROS levels is equally vital as Aβ cascade in AD-related studies.
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In 2015, Kwon et al. synthesized triphenylphosphonium (TPP)-conjugated ceria NPs (TPP-ceria NPs) to use as ROS scavengers. [24] CeO2 can reversibly bind to oxygen atoms, whereas the oxidation state can be changed from Ce 3+ to Ce 4+ on the NPs surface. [133][134][135] TPP is a lipophilic cation that can cross the negatively charged mitochondrial membrane, which makes it a mitochondrial-targeting ligand. [136,137] The in vivo studies of neuronal death suppression were tested with 5XFAD transgenic AD mice. The in vitro cytotoxicity studies have been conducted
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with human neuroblastoma SH-SY5Y cell lines, which displayed the low cytotoxicity for NPs.
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The hydrodynamic particle size of TPP-ceria NPs was approximately 57 nm. The cellular uptake was observed by the confocal fluorescence microscope using fluorescein isothiocyanate (FITC) labeled ceria NPs with and without TPP (Fig. 8). According to fig. 8, the TPP-conjugated ceria NPs showed a higher cellular uptake than bare ceria NPs. The ROS scavenging activity was studied with the superoxide dismutase, and catalase activity assay by investigating the Aβ induced neuronal cell count. The reduction of the Aβ influenced neuronal cell loss was examined by the immunohistochemical analysis of NPs-treated 5XFAD mice. Their results suggested the TPP-ceria
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NPs are an effective neuroprotectant in the 5XFAD mice brain. However, the authors illustrated that the TPP-ceria NPs acted only as an anti-oxidant, which can scavenge the ROS but not as Aβ plaques eliminators.
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J o u r n a l P r e -p r o o f NPs with and without TPP in SH-SY5Y cell lines. The control SH-SY5Y cells were stained with LysoTracker (blue) and MitoTracker (red). The enlarged areas in the square are shown in each image below. The colocalization of FITC-conjugated TPP-ceria/ceria NPs is shown in green. (Scale bar is 20 µm). Figure adapted from Ref. [24] with permissions from the publishers. J o u r n a l P r e -p r o o f by SWCNTs with the presence of mitochondria, suggesting the SWCNTs cytotoxicity is majorly affecting the mitochondria. Moreover, Yang et al. have used SWCNTs to administrate Ach to the brain because SWCNTs can cross the BBB via nerve axon.[144] Also, due to the high affinity of SWCNTs to inorganic and organic molecules, the ACh molecules could easily load on SWCNT by the absorption through acetyl and quaternary ammonium group of ACh. The memory enhancement of SWCNT-ACh was tested with male AD mice, which were damaged by injecting neurotoxin, kainic acid, 24 hrs before the drug treatments. After treating the AD mice with SWCNT-ACh, the AD mice recovered the learning ability to the average level, whereas the bare ACh and bare SWCNTs treated groups have not displayed any recovery. The authors phrased, by keeping the SWCNT dosage below 300 mg/kg, the cytotoxicity towards mitochondria can be diminished. Therefore, Yang et al. claimed their SWCNT-ACh is a better candidate to recover the learning ability in AD mice while using SWCNT in a safe dosage.[144] Luo et al. have investigated the aggregation effect of SWCNTs with Aβ peptide and cross-β structures.[145] The conformational change of the random coiled Aβ peptide into the β sheet amyloid fibers has been identified as the primary mechanism in AD development. The CD spectrum data revealed, in the presence of SWCNTs, the conformational change of Aβ peptide into the β sheet is faster. However, the authors stated the SWCNTs promoted the nucleation at the low concentration of SWCNTs (0.0025 or 0.005 mg mL -1 ), but at the higher concentration (0.1 mg mL -1 ), the amyloid aggregation was inhibited. Luo et al. explained the above discrepancy by saying the SWCNTs fast bind to the Aβ peptides that have undergone the conformational change into parallel-β sheets, not to the cross-β sheets. After the binding of the SWCNTs to the parallel-β sheets, it slows down the conformational change into cross-β stacking, which eventually inhibits J o u r n a l P r e -p r o o f
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the amyloid aggregation. [146,147] However, the SWCNTs-interaction of Aβ is still not well understood.
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In 2014, Liang and co-workers used SWCNTs to reverse the neuronal autophagy. [148] Autophagy is a lysosomal degradative pathway that damages organelle and neurons leading to neurodegenerative disorder AD. [149,150] Therefore, the main goal of Liang and co-workers is to investigate the upregulation of autophagy by using SWCNTs in a transgenic AD mouse model of CRND8 and wild type (WT). [148,151,152] The carboxylic acid-functionalized, less cytotoxic SWCTs, has an average diameter of 1-2 nm. The CRND8 AD mouse models consist of an overexpressed human APP gene that contains two mutations. The overexpression of the APP gene induces the Aβ deposition while decreasing the lysosomal proteolysis. The reduction of lysosomal proteolysis causes amyloidogenesis increasing cognitive impairment. [153] Liang and co-workers discussed the mammalian target of Rapamycin (mTOR) induced autophagy. [148] The treatment of SWCNTs in CRND8 glia cells revealed that SWCNTs were capable of suppressing the autophagy induction, whereas in WT glia displayed a minimal effect. Therefore, the authors stated SWCNTs selectively reversed the APP-originated pathological action of mTOR signaling without affecting normal signaling in WT. Moreover, Liang and co-workers reported, SWCNTs not only reversed the autophagy induction caused by mTOR but also the weakening of lysosomal proteolysis, which leads to lysosomal swelling. Therefore, the autophagy was remarkably weakened by SWCNTs in primary glia in CRND8 mice while reversing the autophagic substrate clearance and autophagy dysfunction.
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Carbon dots (C-dots) are zero-dimensional nanomaterials that have unique optical properties. [154][155][156] C-dots can be synthesized via top-down or bottom-up approaches, which vary the optical and surface properties. [157] C-dots are tiny particles of 1-10 nm in size, which can be used in wider application range, especially in cell penetration studies. [158,159] The high photoluminescence, excitation wavelength-dependent or independent emission, tunable surface, high cell permeability, excellent biocompatibility, and nontoxicity, make C-dots excellent candidates for drug delivery in nanomedicine. [39,[160][161][162] Although C-dots have been used widely in brain targeted tumor studies, the use in neurodegenerative studies, including AD, is deficient.
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Curcumin is a natural polyphenolic antioxidant that scavenges superoxide and hydroxyl radicals.
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Commonly, it is known as an Indian and Chinese spice, Curcuma longa. [166] It has three significant curcuminoids of I, II, and III. Curcumin I (Curcumin) is the major curcuminoid which J o u r n a l P r e -p r o o f is commercially available up to 77%, whereas II (demethoxycurcumin) and III (bisdemethoxycurcumin) availabilities are 17 and 3%, respectively. [167,168] Structurewise, each curcuminoid has a diketone group that further tautomerized into the enol group. Studies have found that during the binding with Aβ, curcumin was found in enol structure. [31] Curcumin provides neuroprotection by activating the primary regulator of the antioxidant response, which is the transcription factor Nrf2. [169] Further, curcumin has identified as an inhibitor for Aβ oligomerization and tau-phosphorylation and also as an inflammatory ROS scavenger and a neutralizer. [170,171] Even though curcumin is a potent neuroprotective agent, its' therapeutic efficacy is limited due to poor BBB/cell penetration, fast metabolism, and lack of bioavailability. [36] Therefore, the bioavailability must be increased to use curcumin as a therapeutic agent. Curcumin NPs and its NP-conjugates are the best possibilities to increase the bioavailability. [172][173][174][175] However, curcumin NPs are still under development, and not many experiments have been carried out for neurodegenerative disease AD.
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In 2013, Baum and co-workers synthesized curcumin NPs by encapsulating curcumin in PEG-PLA. [35] They used a multi-inlet vortex mixture (MIVM) to do a high energetic rapid NP precipitation while avoiding the nanoparticle aggregation. The average curcumin NPs sizes were approximately 55.2-66.2 nm, which were uniform even after one year of storage. The zeta potential was found to be -0. Whereas, the particles higher than 50 nm might enter the brain later, which were found after 80-160 min of administration. Therefore, curcumin NPs have displayed a more extended period of retention time in the brain compared to bulk curcumin revealing the higher bioavailability of the curcumin NPs.