Targetting Exosomes as a New Biomarker and Therapeutic Approach for Alzheimer’s Disease

Figures & data

Figure 1 Biological functions of exosomes. (1) Stimulation of recipient cells by functioning as signal complexes; (2) Transfer of surface receptors or lipids into recipient cells; (3) Delivery of cytoplasmic proteins and nucleic acids via the endocytic pathway; (4) Delivery of cytoplasmic proteins and nucleic acids by membrane fusion.

Abbreviations: miRNA, micro RNA; MVB, multivesicular body.

Figure 2 Exosome and its cargo.

Abbreviations: MHC, major histocompatibility complex; mRNA, messenger RNA; miRNA, microRNA; LncRNA, long non-coding RNA; circRNA, circular RNA.

Table 1 Multiple Roles of Exosomes in AD

Harmful actions	Spreading Aβ and P-tau^Citation10,Citation43,Citation53–Citation57
	Stimulation of aggregation of extracellular Aβ^Citation10,Citation43
	Mediating neuron-to-neuron propagation of oAß^Citation6–Citation10
	Induction of neuronal apoptosis^Citation10
Beneficial actions	Binding extracellular Aβ and promoting its degradation^Citation70,Citation92
	Neutralizing Aβ induced disruption in synaptic plasticity^Citation71
	Carrying nucleic acids with gene expression regulating abilities^Citation90,Citation100–Citation102
	Serving as therapeutic vehicles of drug delivery for AD^Citation108–Citation110

Abbreviations: AD, Alzheimer’s disease; APP, amyloid precursor protein; oAß, ß-amyloid oligomers.

Table 2 Advantages and Challenges of MSC Based Therapy and MSC Exosome Based Therapy

Type of Therapy	Advantages	Challenges
MSC based therapy	Potential of proliferation and differentiation, release of exosomes and other biological factors	Malignant transformation, tumor generation, microvascular obstruction
MSC Exosome based therapy	No apparent adverse effects, capability to cross the blood brain barrier, no vascular obstructive effects, easy to be stored and engineered	Determine the specific benefits and mechanisms of exosome administration, indepth study of exosome contents, potential side effects: tumor promotion

Sardar Sinha M, Ansell-Schultz AS, Civitelli L, et al. Alzheimer’ s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol. 2018;136:41–56. doi:10.1007/s00401-018-1868-129934873

 PubMed Web of Science ®Google Scholar

Zheng T, Wu X, Wei X, et al. The release and transmission of amyloid precursor protein via exosomes. Neurochem Int. 2018;114:18–25. doi:10.1016/j.neuint.2017.12.00929277576

 PubMed Web of Science ®Google Scholar

Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164(6):1226–1232. doi:10.1016/j.cell.2016.01.04326967288

 PubMed Web of Science ®Google Scholar

Winston CN, Goetzl EJ, Akers JC, et al. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement. 2016;3:63–72.

 Google Scholar

Thompson AG, Gray E, Heman-Ackah SM, et al. Extracellular vesicles in neurodegenerative disease - pathogenesis to biomarkers. Nat Rev Neurol. 2016;12(6):346–357. doi:10.1038/nrneurol.2016.6827174238

 PubMed Web of Science ®Google Scholar

Yuyama K, Sun H, Mitsutake S, Igarashi Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J Biol Chem. 2012;287(14):10977–10989. doi:10.1074/jbc.M111.32461622303002

 PubMed Web of Science ®Google Scholar

Yuyama K, Sun H, Sakai S, et al. Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J Biol Chem. 2014;289(35):24488–24498. doi:10.1074/jbc.M114.57721325037226

 PubMed Web of Science ®Google Scholar

An K, Klyubin I, Kim Y, et al. Exosomes neutralize synaptic-plasticity disrupting activity of Aβ assemblies in vivo. Mol Brain. 2013;6(1):47. doi:10.1186/1756-6606-6-4724284042

 PubMed Web of Science ®Google Scholar

Cui GH, Shao SJ, Yang JJ, et al. Designer self-assemble peptides maximize the therapeutic benefits of neural stem cell transplantation for Alzheimer’s disease via enhancing neuron differentiation and paracrine action. Mol Neurobiol. 2016;53:1108–1123. doi:10.1007/s12035-014-9069-y25586060

 PubMed Web of Science ®Google Scholar

Liu S, Liu D, Chen C, et al. MSC transplantation improves osteopenia via epigenetic regulation of notch signaling in lupus. Cell Metab. 2015;22(4):606–618. doi:10.1016/j.cmet.2015.08.01826365178

 PubMed Web of Science ®Google Scholar

Alvarez-Erviti L, Seow Y, Yin H, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29:341. doi:10.1038/nbt.180721423189

 PubMed Web of Science ®Google Scholar

Zhang Y, Chopp M, Meng Y, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122:856–867. doi:10.3171/2014.11.JNS1477025594326

 PubMed Web of Science ®Google Scholar

Wang H, Sui H, Zheng Y, et al. Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the Tau protein through the AKT/GSK-3β pathway. Nanoscale. 2019;11(15):7481–7496. doi:10.1039/C9NR01255A30942233

 PubMed Web of Science ®Google Scholar