Neurodegenerative diseases are characterized by loss of neurons in the central or peripheral nervous system which leads to losing their function and structure over time. Two common forms of neurodegenerative diseases are Alzheimer Disease (AD) and Parkinson Disease (PD). AD is the major cause of dementia in the world, accounting for 60%-70% of all demented cases [1]. It is related to permanent and progressive loss of memory and cognitive functions. The senile plaques containing amyloid β (Aβ) deposits and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein are two pathological hallmarks of AD. Accordingly, there are two generally accepted hypotheses of the Aβ and the tau hypotheses. Based on the amyloid hypothesis, the imbalance between the generation and the clearance of Aβ is the main cause of AD [2, 3]. Aβ is formed by the continuous proteolytic cleavage of the amyloid precursor protein (APP) by β-secretase (beta-site amyloid precursor protein cleaving enzyme1, BACE1), and γ-secretase (consisting of presenilin1 and presenilin2). 

Tau protein is a microtubule-stabilizing protein that modulates axonal transport. When tau hyperphosphorylates, it separates from microtubules and aggregates into insoluble fibers. NFTs are made of the hyperphosphorylated and dephosphorylated forms of tau. It is believed that tauopathies contribute to the severity of AD [4]. 

PD is the most common movement disorder. It affects almost 1% of the people over 50 years of age [5]. PD patients usually show disorders related to movement, including resting tremor, muscle rigidity, and cognitive malfunction as the disease advances. PD is characterized by Lewy bodies (LBs) in the substantia nigra pars compacta (SNpc) and striatum and progressive losing of dopaminergic neurons. LBs mostly comprise filamentous α-synuclein (α-syn). In PD patients, α-syn becomes abnormally phosphorylated and aggregated [6]. It has been suggested that LB impairs pathways, including vesicle trafficking or activating neuroinflammation [7]. 

Substantial evidence suggests that exosomes work as a vesicular conveyor for intercellular transmission in neurodegenerative disorders [8]. Recent studies indicate that exosome transport disease particles such as α-syn [9, 10], Aß, and prions from their original cells to other cells [11, 12]. Increasing documentation shows that microRNA (miRNA) is an important factor in AD and PD pathogenesis. In this regard, miRNA, a class of non-coding RNAs, have been considered as important regulators for post-transcriptional gene expression by either suppressing translation or degrading target mRNAs [13]. 

Since their findings, miRNAs have been recognized as the modulator mostly implicated in many vital biological processes, including development, growth, differentiation, and neurodegeneration [14]. One miRNA could choose many genes and a single gene could be regulated by several miRNAs. This feature makes miRNAs a potential tool to study multifactorial diseases like AD [15].

Exosomes 

Molecular content of exosomes

Exosomes have a complex and unique composition with various biomolecules (such as proteins, lipids, mRNAs, microRNAs [miRNAs], and DNA) [20, 21]. According to the latest ExoCarta database, almost a variety of 194 lipids, 4563 proteins, 1639 mRNAs, and 764 miRNAs have been determined in exosomes of several organisms [22]. The content of exosomes can be categorized into two groups: constitutive molecules and cargo molecules. Constitutive molecules play a crucial role in the structural and functional properties of exosomes and based on the type of the derived cell, they are unique to the exosome. Cargo molecules include lipids, proteins, and various genetic materials that are resorted, encapsulated, and transported by exosomes. Cargo molecules are highly heterogeneous and vary based on the origin of the cell and the pathological or physiological conditions when exosomes create. Protein cargoes include heat shock proteins (Hsc70, Hsp90) and different types of tetraspanins (CD9, CD63, CD81, and CD82), flotillin, Rab GTPases, Alix, Tsg101; lipid cargoes have an essential role in regulating exosomal sorting of small RNAs and proteins. The genetic material cargoes consist of DNA and different types of RNA (mRNA, miRNA, rRNA, circular RNA, and long non-coding RNA [lnRNA]) [23].

Although exosomes were initially considered as cellular waste (garbage bags) or by-products of cell homeostasis, new data elucidate that exosomes are an alternative way to eliminate waste products from cell damage and maintain cellular homeostasis [24, 25]. The most attractive function of exosomes is as vehicles of lipids and proteins, which influence downstream signaling events in recipient cells and affect different features of physiology and cell behavior, such as nerve regeneration, synaptic function, and behavior [26].

It has been found that these extracellular vesicles have various functions in many cellular processes. They carry essential biological molecules from one cell to the other, regulate the microenvironment, and the genetic and epigenetic systems of cells [27]. They also participate in cell-cell communication, signal transduction, cell maintenance, and immune responses [28-32]. In addition, evidence shows that exosomes are also interestingly involved in angiogenesis, tumorigenesis, metastasis of tumor cells, and the transformation of normal cells into tumor cells. It has been reported that they respond to therapy through the transfer of oncogenes and oncomiRNAs between cancer cells [33, 34].

Evidence has revealed that exosomes have both positive and negative effects on the nervous system. According to studies, exosomes help develop the formation of the myelin sheath, growth of neurite, and survival of neurons. They are, therefore, important parameters in the regeneration and repair of tissues. Besides, exosomes in the CNS contain pathogenic proteins, such as Aβ peptide, and α-syn that may aid in disease progression. Therefore, exosomes in the brain through the transfer of misfolded proteins can also play a negative role in the creation of CNS diseases, such as stroke, AD, PD, and the like [35].

Exosome in Neurodegeneration 

Alzheimer disease

Exosomes play a threatening role in the extension of toxic Aß pathology. Several studies have noted that exosomes serve as carriers for Aß transportation. A notable report by Rajendran et al. showed that the cleavage of APP by ß secretase happens in the particular endosomes and is transferred into multivesicular bodies (MVBs) from its original release location in company with exosomes. They reported that exosomal proteins such as Alix and flotillin-1 can accumulate around amyloid plaques in the brains of AD patients [36]. Further studies have shown that they may increase Aß production and deposition and inhibit Aß clearance [37]. 

In addition, exosomes increase abnormal tau phosphorylation. It has been reported that they carry phosphorylated tau protein and may be accountable for the extension of tau between cells in neurodegenerative AD conditions. Elevated levels of exosome-associated phosphorylated tau are easily detected in the cerebrospinal fluid (CSF) samples of early AD patients and reduce as the disease develops despite the increase in the total level of the protein, maybe because of separation of tau from the exosome fraction [38].

Parkinson disease

It has been shown that exosomes are involved in α-syn aggregation, transportation to the extracellular environment, and release of its toxic forms. Absorption of exosomes full of α-syn has been demonstrated to cause death in nearby neurons and leads to their dysfunction [6, 9]. 

Important evidence showed that mutations in some endocytic genes like leucine-rich receptor kinase 2 (LRRK2), and vacuolar sorting protein 35 (VPS35) are associated with PD. Based on studies, a mutation in LRRK2 causes an abnormal elevation in the quantity of morphologically distinguished MVBs. The creation of many MVBs could be the potential cause of the collection of exosomes loaded with the toxic form of α-syn and extension of the disease to adjacent neurons [39].

Exosome in neuroinflammation

Neuroinflammation is considered a chronic inflammation of the central nervous system. It is identified by the activation of astrocytes and microglia. Activated microglial cells are required in an inflammatory response, stimulating the release of cytokines and chemokines, tumor necrosis factor-α (TNF-α), TNF-β, nuclear factor-ĸB, and enzymes like 5-lipooxygenase (5-LOX), 12-LOX, and cyclooxygenase 2 (COX-2) [38].

Exosomes have the key role as cargo of inflammatory molecules. Therefore, they are considered inflammatory mediators. It has been reported that they may promote neuroinflammation due to communication between neurons and glia [38, 40]. 

Besides, neuroinflammation can trigger Aβ pathogenesis and tau hyperphosphorylation which are two important hallmarks of AD. Gupta and Pallim have shown that Aβ is packaged into exosomes and extends between cells, beginning an inflammatory cascade [38]. In the early stage, the stimulation of microglia by Aβ has a neuroprotective effect because it can phagocyte and degrade Aβ. The microglia activation by astrocyte secreted ATP cause to release of exosomes as a protective strategy to prevent astrocyte signaling [41]. In the later stage, microglia release exosomes comprising pro-IL1 b, active caspase-1, and soluble toxic Aβ. All of them damage nerve cells [42].

Also, it has been shown that astrocytes can internalize α-syn deposits. This phenomenon is related to the later formation of inclusion bodies, as found in PD patients’ brains and the beginning of an inflammatory response. moreover, exosomes released by activated microglia are the important moderator of neurodegeneration, which is induced by α-syn [43].

Exosomes as diagnostic and therapeutic biomarkers

In recent years, various studies have revealed that exosomes and their cargo molecules are indicative of pathophysiological conditions and a better reflection of the cellular processes. Recent studies show that they can be used as valuable prognostic and diagnostic biomarkers of various diseases [16], such as chronic inflammation [44], cardiovascular and renal diseases [45, 46], lipid metabolic diseases [47], cancer progression [48], and neurodegenerative diseases [49]. 

To date, there is still no cure for neurodegenerative diseases such as AD and PD that can alter or stop its development, although, there are various medications for AD and PD that can improve symptoms in some patients. It should be noted that many of these drugs have side effects.

Discovering new biomarkers can provide an early diagnosis of AD, which is very important and valuable for stopping and delaying the progression of the disease [37]. Exosomes can be detected in CSF and peripheral body fluids and can cross the blood-brain barrier (BBB) and are greatly stable in the peripheral circulation. Studies have shown that the content of exosomes will change with the occurrence of disease. Therefore, using exosomes as an appealing target for biomarker development in CNS diseases is an interesting prospect due to its potential to track disease progression and enable early diagnosis and treatment optimization [35].

Recent studies propose that the existence of Aβ1-42 or tau in the CSF exosomes can be a useful diagnostic indicator for the early diagnosis of AD. In these patients, plasma and CSF exosomes contain full-length tau contrary to the healthy people [50]. Also, the existence of Aβ1-42 in CSF exosomes could be a sensitive scale for recognizing AD. The detection of both tau and Aβ 1–42 in CSF can help diagnose AD 10 years before the clinical symptoms [51]. Interestingly, new studies show that the level of each exosomal biomarker and the respective CSF biomarker are strongly correlated [52]. 

In Alzheimer disease, miRNA changes may be found both in the brain, CSF, and other biological fluids. It has been reported that miRNA sequences can be deregulated in the peripheral blood of AD patients. Several studies have determined differences in miRNA concentrations between normal people and Alzheimer disease blood, making its potential as a diagnostic procedure. It is worth noting that miRNAs exhibit higher sensitivity levels compared to protein biomarkers, which is mainly a consequence of the amplification of polymerase chain reaction (PCR) [53-56]. The role of exosome in clearance is vital in AD [57]. Because of this important ability to elevate Aβ clearance, it has been suggested that exosomes have potential in the treatment of AD [58]. 

In Parkinson disease, recent research has been reported multiple roles for exosomes, including neurotoxic and neuroprotective roles, diagnostic biomarkers, and the application as a drug delivery system [59, 60]. 

Gui et al. and Cao et al. in separate studies appraised the existence of miRNAs in exosomes from the CSF and serum of PD patients [61, 62]. A different profile of significantly upregulated and downregulated miRNAs in exosomes of PD patients in comparison to healthy people was analyzed. These miRNAs can regulate genes that are involved in different pathways for PD.

Result of recent studies show that some miRNAs, including miRNA-155, miRNA-7, miRNA-124, miRNA-205, miRNA-34b/c, and miRNA-7116-5p have therapeutic potentials and miRNA-1, miRNA-19b-3p, miRNA-153, miRNA-409-3p, miRNA-10a-5p, miRNA-19b, miRNA-195, and miRNA-24 are important biomarkers in different diseases. These findings strongly support the idea that miRNA exosomes are potentially a valuable diagnostic and therapeutic tool in PD.

Result of recent studies on miRNA-155, miRNA-7, miRNA-124, miRNA-205, miRNA-34b/c, and miRNA-7116-5p as therapeutic potential, and miRNAs, miRNA-1, miRNA-19b-3p, miRNA-153, miRNA-409-3p, miRNA-10a-5p, miRNA-19b, miRNA-195, and miRNA-24 as biomarker miRNAs strongly indicate the diagnostic and therapeutic value of miRNA exosomes in PD [61-64]. Lemprière mentioned exosomal α-syn as a biomarker for PD [65].

It is suggested that exosomes (synthesized or obtained from the natural cell) can be applied as nano-particle tools for the delivery of therapeutic drugs, proteins, miRNA, and siRNAs. Exosomes can pass the BBB and enter the targeted cells to release their cargoes for therapeutic roles [66, 67]. Qu et al. reported that loaded exosomes with dopamine had a better therapeutic effect with less toxicity than free dopamine by a structured intravenous administration in the PD mice model [68]. These findings, therefore, show that the PD animal models benefit from the transfer of genetic materials such as miRNAs within mesenchyme stem cells (MSCs)-derived exosomes. This method is therefore considered an effective tool, provides a potential treatment for PD. Therefore, understanding how these miRNAs exosomes communicate with the cells and molecules in PD is substantial. Although increasing evidence for the role of exosomes in the pathogenesis of PD and AD has been found, the mechanisms within the molecules that control and modulate exosome secretion, biogenesis, and communication with recipient cells should be still defined [69].

Conclusion

The discovery of exosomes as diagnostic biomolecules and therapeutic drug delivery systems in many diseases such as neurodegenerative diseases are highly promising. Above all, isolating safer exosomes for diagnosis, therapy, and prognosis requires more standardized purification technologies that should be progressed.

Ethical Considerations

Compliance with ethical guidelines

All study procedures were in compliance with the ethical guidelines of the Declaration of Helsinki, 2013.

Funding

This research received no specific grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions

Both authors equally contributed in preparing this article.

Conflict of interest

The authors declared no conflict of interest.

 

References

1.Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement. 2013; 9(1):63-75.e2. [DOI:10.1016/j.jalz.2012.11.007] [PMID]

2.Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet. 2011. 377(9770):1019-31. [DOI:10.1016/S0140-6736(10)61349-9]

3.Jafari A, Noursadeghi E, Khodagholi F, Saghiri R, Sauve R, Aliaghaei A, et al. Brain mitochondrial ATP-insensitive large conductance Ca⁺²-activated K⁺ channel properties are altered in a rat model of amyloid-β neurotoxicity. Exp Neurol. 2015; 269:8-16. [DOI:10.1016/j.expneurol.2014.12.024] [PMID]

4.Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005; 1739(2-3):198-210. [DOI:10.1016/j.bbadis.2004.09.008] [PMID]

5.Alves G, Forsaa EB, Pedersen KF, Dreetz Gjerstad M, Larsen JP. Epidemiology of Parkinson’s disease. J Neurol. 2008; 255(Suppl 5):18-32. [DOI:10.1007/s00415-008-5004-3] [PMID]

6.Russo I, Bubacco L, Greggio E. Exosomes-associated neurodegeneration and progression of Parkinson’s disease. Am J Neurodegener Dis. 2012; 1(3):217-25. [PMID] [PMCID]

7.Hallett PJ, Engelender S, Isacson O. Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease. J Neuroinflammation. 2019; 16(1):153. [DOI:10.1186/s12974-019-1532-2] [PMID] [PMCID]

8.Schneider A, Simons M. Exosomes: Vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res. 2013; 352(1):33-47. [DOI:10.1007/s00441-012-1428-2] [PMID] [PMCID]

9.Tsunemi T, Hamada K, Krainc D. ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein. J Neurosci. 2014; 34(46):15281-7. [DOI:10.1523/JNEUROSCI.1629-14.2014] [PMID] [PMCID]

10.Grey M, Dunning CJ, Gaspar R, et al. Acceleration of α-synuclein aggregation by exosomes. J Biol Chem 2015; 290(5):2969-82. [DOI:10.1074/jbc.M114.585703] [PMID] [PMCID]

11.Kalani A, Tyagi A, Tyagi N. Exosomes: Mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol. 2014; 49(1):590-600. [DOI:10.1007/s12035-013-8544-1] [PMID] [PMCID]

12.Yuyama K, Hui S, Seigo U, Sakai S, Hanamatsu H, Mioka T, et al. A potential function for neuronal exosomes: Sequestering intracerebral amyloid-β peptide. FEBS Lett. 2015; 589(1):84-8. [DOI:10.1016/j.febslet.2014.11.027] [PMID]

13.Maoz R, Garfinkel BP, Soreq H. Alzheimer’s disease and ncRNAs. In: Delgado-Morales R. (editors) Neuroepigenomics in Aging and Disease. Adv Experim Med Biol. Springer, Cham; 2017; 978. [DOI:10.1007/978-3-319-53889-1_18] 

14.Hammond SM. An overview of microRNAs. Adv Drug Deliv Rev. 2015; 87:3-14. [DOI:10.1016/j.addr.2015.05.001] [PMID] [PMCID]

15.Iqbal K, Grundke-Iqbal I. Alzheimer’s disease, a multifactorial disorder seeking multitherapies. Alzheimers  Dement. 2010; 6(5):420-4. [DOI:10.1016/j.jalz.2010.04.006] [PMID] [PMCID]

16.Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: Biogenesis, biologic function and clinical potential. Cell  Biosci. 2019; 9(1):19. [DOI:10.1186/s13578-019-0282-2] [PMID] [PMCID]

17.Kastelowitz N, Yin H. Exosomes and microvesicles: identification and targeting by particle size and lipid chemical probes. Chembiochem. 2014; 15(7):923-8. [DOI:10.1002/cbic.201400043] [PMID] [PMCID]

18.Théry C, Zitvogel L, Amigorena S. Amigorena, Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. [DOI:10.1038/nri855] [PMID]

19.Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987; 262(19):9412-20. [PMID]

20.Waldenström A, Gennebäck N, Hellman U, Ronquist G. Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells. PloS One. 2012; 7(4):e34653. [DOI:10.1371/journal.pone.0034653] [PMID] [PMCID]

21.Simpson RJ, Lim JW, Moritz RL, Mathivanan S. Exosomes: Proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009; 6(3):267-83. [DOI:10.1586/epr.09.17] [PMID]

22.Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: Database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012; 40(Database issue):D1241-4. [DOI:10.1093/nar/gkr828] [PMID] [PMCID]

23.Wahlgren J, Statello L, Skogberg G, Telemo E, Valadi H. Delivery of small interfering RNAs to cells via exosomes. Methods Mol Biol. 2016; 1364:105-25. [DOI:10.1007/978-1-4939-3112-5_10] [PMID]

24.Hessvik NP, Øverbye A, Brech A, et al. PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell Mol Life Sci. 2016; 73(24):4717-37. [DOI:10.1007/s00018-016-2309-8] [PMID]

25.Baixauli F, López-Otín C, Mittelbrunn M. Exosomes and autophagy: Coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. 2014; 5:403. [DOI:10.3389/fimmu.2014.00403] [PMID] [PMCID]

26.Arscott WT, Tandle AT, Zhao S, Shabason JE, Gordon IK, Schlaff CD, et al. Ionizing radiation and glioblastoma exosomes: Implications in tumor biology and cell migration. Transl Oncol. 2013; 6(6):638-48. [DOI:10.1593/tlo.13640] [PMID] [PMCID]

27.Gougelet A. Exosomal microRNAs as a potential therapeutic strategy in hepatocellular carcinoma. World J Hepatol. 2018; 10(11):785-9. [DOI:10.4254/wjh.v10.i11.785] [PMID] [PMCID]

28.Chen R, Xu X, Tao Y, et al. Exosomes in hepatocellular carcinoma: A new horizon. Cell Commun Signal. 2019; 17(1):1-11. [DOI:10.1186/s12964-018-0315-1] [PMID] [PMCID]

29.van Niel G, Porto-Carreiro I, Simoes S, et al. Exosomes: A common pathway for a specialized function. J Biochem. 2006; 140(1):13-21. [DOI:10.1093/jb/mvj128] [PMID]

30.Schorey JS, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic. 2008; 9(6):871-81. [DOI:10.1111/j.1600-0854.2008.00734.x] [PMID] [PMCID]

31.Greening DW, Gopal SK, Xu R, et al. Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol. 2015; 40:72-81. [DOI:10.1016/j.semcdb.2015.02.009] [PMID]

32.Bobrie A, Colombo M, Raposo G, Théry C. Exosome secretion: Molecular mechanisms and roles in immune responses. Traffic. 2011; 12(12):1659-68. [DOI:10.1111/j.1600-0854.2011.01225.x] [PMID]

33.Guo W, Gao Y, Li N, Shao F, Wang C, Wang P, et al. Exosomes: New players in cancer (Review). Oncol Rep. 2017; 38(2):665-75. [DOI:10.3892/or.2017.5714] [PMID] [PMCID]

34.Kharaziha P, Ceder S, Li Q, Panaretakis T. Tumor cell-derived exosomes: A message in a bottle. Biochim Biophys Acta. 2012; 1826(1):103-11. [DOI:10.1016/j.bbcan.2012.03.006] [PMID]

35.Liu W, Bai X, Zhang A, Huang J, Xu S, Zhang J. Role of exosomes in central nervous system diseases. Front Mol Neurosci. 2019; 12:240. [DOI:10.3389/fnmol.2019.00240] [PMID] [PMCID]

36.Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, et al. Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006; 103(30): 11172-7. [DOI:10.1073/pnas.0603838103] [PMID] [PMCID]

37.Cai ZY, Xiao M, Quazi SH, Ke ZY. Exosomes: A novel therapeutic target for Alzheimer’s disease? Neural Regen Res. 2018; 13(5):930-5. [DOI:10.4103/1673-5374.232490] [PMID] [PMCID]

38.Gupta A, Pulliam L. Exosomes as mediators of neuroinflammation. J Neuroinflammation. 2014; 11:68. [DOI:10.1186/1742-2094-11-68] [PMID] [PMCID]

39.Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, et al. GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet. 2010; 6(4):e1000902. [DOI:10.1371/journal.pgen.1000902] [PMID] [PMCID]

40.de Rivero Vaccari JP, Brand F 3rd, Adamczak S, Lee SW, Perez-Barcena J, Wang MY, et al. Exosome-mediated inflammasome signaling after central nervous system injury. J Neurochem. 2016; 136(Suppl 1):39-48. [DOI:10.1111/jnc.13036] [PMID] [PMCID]

41.Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci. 2008; 28(16):4283-92. [DOI:10.1523/JNEUROSCI.4814-07.2008] [PMID] [PMCID]

42.Trotta T, Antonietta Panaro M, Cianciulli A,Mori G, Di Benedetto A, Porro C. Microglia-derived extracellular vesicles in Alzheimer’s Disease: A double-edged sword. Biochem Pharmacol. 2018; 148:184-92. [DOI:10.1016/j.bcp.2017.12.020] [PMID]

43.Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012; 7:42. [DOI:10.1186/1750-1326-7-42] [PMID] [PMCID]

44.Lässer C, O’Neil SE, Shelke GV, Sihlbom C, Hansson SF, Gho YS, et al. Exosomes in the nose induce immune cell trafficking and harbour an altered protein cargo in chronic airway inflammation. J Transl Med. 2016. 14(1):181. [DOI:10.1186/s12967-016-0927-4] [PMID] [PMCID]

45.Gonzalez-Calero L, M. Martin-Lorenzo, Alvarez-Llamas G. Exosomes: A potential key target in cardio-renal syndrome. Front Immunol. 2014; 5:465. [DOI:10.3389/fimmu.2014.00465] [PMID] [PMCID]

46.Kishore R, Garikipati VNS, Gumpert A. Tiny shuttles for information transfer: exosomes in cardiac health and disease. J Cardiovasc Transl Res. 2016; 9(3):169-75. [DOI:10.1007/s12265-016-9682-4] [PMID] [PMCID]

47.Record M, Poirot M, Silvente-Poirot S. Emerging concepts on the role of exosomes in lipid metabolic diseases. Biochimie. 2014; 96:67-74. [DOI:10.1016/j.biochi.2013.06.016] [PMID]

48.Salem KZ, Moschetta M, Sacco A, Imberti L, Rossi G, Ghobrial IM, et al. Exosomes in tumor angiogenesis. In: Ribatti D. (eds) Tumor Angiogenesis Assays. Methods Mol Biol. 2016; 1464:25-34. [DOI:10.1007/978-1-4939-3999-2_3] [PMID]

49.Howitt J, Hill AF. Exosomes in the pathology of neurodegenerative diseases. J Biol Chem. 2016; 291(52):26589-97. [DOI:10.1074/jbc.R116.757955] [PMID] [PMCID]

50.Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Neural Regeneration Research. 2016; 15(7):673-84. [DOI:10.1016/S1474-4422(16)00070-3]

51.Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, et al. Cerebrospinal fluid tau and β-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. 2003; 60(12):1696-702. [DOI:10.1001/archneur.60.12.1696] [PMID]

52.Jia L, Qiu Q, Zhang H, Chu L, Du Y, Zhang J. Concordance between the assessment of Aβ42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement. 2019; 15(8):1071-80. [DOI:10.1016/j.jalz.2019.05.002] [PMID]

53.Swarbrick S, Wragg N, Ghosh S, Stolzing A. Systematic review of miRNA as biomarkers in Alzheimer’s disease. Mol Neurobiol. 2019; 56(9):6156-67. [DOI:10.1007/s12035-019-1500-y] [PMID] [PMCID]

54.Kumar S, Vijayan M, Bhatti JS, Reddy PH. MicroRNAs as peripheral biomarkers in aging and age-related diseases. Prog Mol Biol Transl Sci. 2017; 146:47-94. [DOI:10.1016/bs.pmbts.2016.12.013] [PMID]

55.Condrat CE, Thompson DC, Barbu MG, Bugnar OL, Boboc A, Cretoiu D, et al. miRNAs as biomarkers in disease: Latest Findings regarding their role in diagnosis and prognosis. Cells. 2020; 9(2):276. [DOI:10.3390/cells9020276] [PMID] [PMCID]

56.Wang T, Xiao S, Liu Y, Lin Z, Su N, Li X, et al. The efficacy of plasma biomarkers in early diagnosis of Alzheimer’s disease. Int J Geriatr Psychiatry. Psychiatry 2014; 29(7):713-9. [DOI:10.1002/gps.4053] [PMID]

57.Soria FN, Pampliega O, Bourdenx M, Meissner WG, Bezard E, Dehay B. Exosomes: An unmasked culprit in neurodegenerative diseases. Front Neurosci. 2017; 11:26. [DOI:10.3389/fnins.2017.00026] [PMID] [PMCID]

58.Lakshmi S, Essa MM, Hartman RE, Guillemin GJ, Sivan S, Elumalai P. Exosomes in Alzheimer’s disease: Potential role as pathological mediators, biomarkers and therapeutic targets. Neurochem Res. 2020; 45(11):2553-9. [DOI:10.1007/s11064-020-03111-1] [PMID]

59.Longoni B, Fasciani I, Kolachalam S, Pietrantoni I, Marampon F, Petragnano F, et al. Neurotoxic and neuroprotective role of exosomes in Parkinson’s disease. Curr Pharm Des. 2019; 25(42):4510-22. [DOI:10.2174/1381612825666191113103537] [PMID]

60.Wu X, Zheng T, Zhang B. Exosomes in Parkinson’s Disease. Neurosci Bull. 2017; 33(3):331-8. [DOI:10.1007/s12264-016-0092-z] [PMID] [PMCID]

61.Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget. 2015; 6(35):37043-53. [DOI:10.18632/oncotarget.6158] [PMID] [PMCID]

62.Cao XY, Lu JM, Zhao ZQ, Li MC, Lu T, An XS, et al. MicroRNA biomarkers of Parkinson’s disease in serum exosome-like microvesicles. Neurosci Lett. 2017; 644:94-9. [DOI:10.1016/j.neulet.2017.02.045] [PMID]

63.Miñones-Moyano E, Porta S, Escaramís G, Rabionet R, Iraola S, Kagerbauer B, et al. MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet. 2011; 20(15):3067-78. [DOI:10.1093/hmg/ddr210] [PMID]

64.Saraiva C, Paiva J, Santos T, Ferreira L, Bernardino L. MicroRNA-124 loaded nanoparticles enhance brain repair in Parkinson’s disease. J Control Release. 2016; 235:291-305. [DOI:10.1016/j.jconrel.2016.06.005] [PMID]

65.Lemprière S. Exosomal α-synuclein as a biomarker for Parkinson disease. Nat Rev Neurol. 2020; 16(5):242-3. [DOI:10.1038/s41582-020-0349-z] [PMID]

66.Lai CP, Breakefield XO. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Frontin Physiol. 2012; 3:228. [DOI:10.3389/fphys.2012.00228] [PMID] [PMCID]

67.Aryani A, Denecke B. Exosomes as a nanodelivery system: A key to the future of neuromedicine? Mol Neurobiol. 2016; 53(2):818-34. [DOI:10.1007/s12035-014-9054-5] [PMID] [PMCID]

68.Qu M, Lin Q, Huang L, Fu Y, Wang L, He S, et al. Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson’s disease. J Control Release. 2018; 287:156-66. [DOI:10.1016/j.jconrel.2018.08.035] [PMID]

69.Müller T. Drug therapy in patients with Parkinson’s disease. Transl Neurodegener. 2012; 1(1):10. [DOI:10.1186/2047-9158-1-10] [PMID] [PMCID]